Bicyclic compounds and their use in the treatment of cancer

ABSTRACT

The present disclosure is directed to novel compounds of Formula I and pharmaceutically acceptable salts, solvates, solvates of the salt and prodrugs thereof, useful in the prevention (e.g., delaying the onset of or reducing the risk of developing) and treatment (e.g., controlling, alleviating, or slowing the progression of) of cancer, including glioblastoma, bone cancer, head and neck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer, gastric cancer, intestinal cancer, colon cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, and prostate cancer. The compounds of the disclosure are selective antagonists of the EP4 receptor and useful treatment of various diseases that may be ameliorated with blockade of PGE2-mediated signaling.

CROSS-REFERENCE

This claims the benefit of U.S. Provisional Application No. 62/486,765,filed Apr. 18, 2017, which is hereby incorporated by reference in itsentirety.

BACKGROUND OF THE INVENTION

The present disclosure is directed to heteroaryl carboxamidederivatives, pharmaceutical compositions containing such compounds, aswell as methods for preventing and treating cancer using such compounds.

Prostaglandin E2 (PGE2) is an endogeneous molecule that, through itsagonism of the EP4 receptor and activation of the resulting signalingcascade, has been shown to play a key role in the resolution ofinflammation (Chen et al., British J. Pharmacol. 2010, 160, p. 292) andin the suppression of T cell receptor signaling (Wiemer et al., J.Immunology 2011, 187, p. 3663). While this dampening of inflammatoryresponse is pivotal for the prevention of excessive cellular damagefollowing the successful mounting of an inflammatory response that hasbeen triggered, for example, by the invasion of a foreign pathogen, ithas been demonstrated that some tumors can also hijack this mechanism asa way of creating an immunosuppressive microenvironment within whichtumor cells can proliferate (Whiteside, Expert Opin. Bio. Th. 2010, 10,p. 1019).

Indeed, one of the major hallmarks of an immunosuppressive tumormicroenvironment is the presence of large amount of myeloid-derivedsuppressor cells (MDSCs) and type-2 tumor-associated macrophages (TAMs),which in turn, are significantly associated with poor overall survivalin patients with gastric, ovarian, breast, bladder, hepatocellularcarcinoma (HCC), head-and-neck, and other types of cancers (Qian et al.,Cell. 2010, 141, p. 39; Gabitass et al., Cancer Immunol. Immunother.2011, 60, p. 1419). Engagement of EP4 receptors on immature monocytes byPGE2, which is produced in significantly greater quantities by tumorcells (Ochs et al., J. Neurochem. 2016, 136, p. 1142; Zelenay, S. etal., Cell 2015, 162, p. 1257), have been demonstrated to skew thedifferentiation of these immature monocytes towards bothimmunosuppressive MDSC and TAM lineages (Mao, et al., Clin. Cancer Res.2014, 20, p. 4096; Wang et al., Trends in Molecular Medicine 2016, 22,p. 1).

Furthermore, recent studies have revealed that tumor cells in someinstancesalso mediate the upregulation of indoleamine 2,3-dioxygenase(IDO) and/or tryptophan 2,3-deoxygenase (TDO) activity in thesurrounding tumor microenvironment via stimulation of the EP4 receptorby PGE2 (Ochs et al., J. Neurochem. 2016, 136, p. 1142; Hung et al.,Breast Cancer Research, 2014, 16, p. 410). Since tryptophan, thesubstrate of the IDO and TDO enzymes, is essential for the proliferationand activation of cyototoxic Teff cells, and kyneurenine, the product ofthe IDO and TDO enzymes, is essential for the proliferation andactivation of immunosuppressive Treg cells (Dounay et al., J. Med. Chem.2015, 58, p. 8762), inhibition of the IDO and/or TDO activity representsa promising avenue for the treatment of various cancers (Jochems et al.,Oncotarget 2016, 7, p. 37762). In fact, increased overall response ratein patients with advanced stage TIM or IV melanoma have been reportedwith epacadostat, a potent and selective IDO inhibitor from Incyte, whenused in combination with pembrolizumab. In light of all theseobservations and studies, it is therefore reasonable that antagonism ofEP4 would represent a rational and efficacious approach for thetreatment of advanced cancer, both as a single agent and in combinationwith other anti-cancer therapies.

SUMMARY OF THE INVENTION

Some embodiments provided herein describe compounds of Formula I, whichare potent and selective antagonists of the EP4 receptor,pharmaceutically acceptable salts of Formula I, pharmaceuticallyacceptable compositions comprising such compounds, and the use of suchcompounds in the treatment of various diseases that may be amelioratedwith the blockade of PGE2-mediated signaling, in particular cancer. Forthe treatment of cancer, compounds of Formula I, in some instances, areused alone or in combination with other cancer therapies, for example,radiation, antibodies to cytotoxic t-lymphocyte antigen 4 (i.e.anti-CTLA4 agents such as ipilimumab, or the like), antibodies toprogrammed death-ligand 1 (i.e. anti-PD-L1 agents such as atezolizumab,avelumab, or the like), antibodies to programmed cell death protein 1(i.e. anti-PD-1 agents such as nivolumab, pembrolizumab, or the like) orcytotoxic agents (i.e. alkylating agents such as cisplatin, dacarbazine,chlorambucil, or the like; anti-metabolites such as methotrexate,fludarabine, gemcitabine, or the like; anti-microtubule agents such asvinblastine, paclitaxel, or the like; topoisomerase inhibitors such astopotecan, doxorubicin, or the like; and others). Other embodimentsprovided herein describe processes for the preparation of the compoundsof Formula I, as well as for the preparation of intermediates used inthe synthesis of the compounds described herein.

Some embodiments provided herein describe compounds of Formula I:

or a pharmaceutically acceptable salt, solvate, solvate of the salt,hydrate, a single stereoisomer, a mixture of stereoisomers, a racemicmixture of stereoisomers, or prodrug thereof;

wherein

-   -   Ar is an aryl or a heteroaryl, wherein said aryl and said        heteroaryl are each optionally substituted with 1 to 3        substituents independently selected from: (a) C₁-C₆ alkyl, (b)        C₃-C₇ cycloalkyl, (c) heterocycle, (d) aryl, (e) heteroaryl, (f)        halogen, (g) CN, (h) OR^(b), (i) N(R^(b))C(═O)R^(c), (j)        C(═O)N(R^(b))(R^(c)), (k) S(═O)_(m)R^(b), (l)        S(═O)₂N(R^(b))(R^(c)), (m) N(R^(b))S(═O)₂R^(c), (n) SF₅, and (o)        C₁-C₆ haloalkyl;    -   W is selected from: (a) C(═O)OR⁵, (b) C(═O)NHOH, (c)        S(═O)₂NHR^(b), (d) S(═O)₂NHC(═O)R^(b), (e)        NHC(═O)NHSO₂R^(b), (f) 1H-tetrazole, (g)        1,2,4-oxadiazol-5(4H)one, (h) 1,2,4-thiadiazol-5(4H)one, (i)        1,2,4-oxadiazole-5(4H)-thione, (j) 1,2,4-triazole-5(4H)-one, (k)        tetrazol-5(4H)-one, and (l) C(═O)NHS(═O)₂R^(b);    -   X¹, X², X³, X⁴, and X⁵ are each independently N or CR^(a),        wherein not more than 2 of X¹, X², X³, X⁴, and X⁵ are N;    -   Y is selected from: (a) a bond, (b) (CH₂)_(n) wherein 1 to 4        hydrogen atoms may be replaced by R^(a′), (c) O, and (d) NR^(b);    -   Z is (CH₂)_(n), wherein 1 to 4 hydrogen atoms may be replaced by        R^(a′);    -   R¹ and R² are independently selected from: (a) H, (b) C₁-C₆        alkyl, (c) C₃-C₆ cycloalkyl, and (d) C₁-C₆ haloalkyl, wherein R²        is not H; or        -   R¹ and R² taken together represent —(CH₂)_(n)—,            —(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or            —(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—;    -   R³ and R⁴ are independently selected from: (a) H, (b) C₁-C₆        alkyl, (c) C₃-C₆ cycloalkyl, (d) aryl, (e) heteroaryl, (f)        halogen, (g) C₁-C₆ haloalkyl; or        -   R³ and R⁴ taken together represent —(CH₂)_(n)—,            —(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or            —(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—;    -   or R¹, R², R³ and R⁴ above are selected as follows:        -   R¹ is selected from H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and            C₁-C₆ haloalkyl;        -   R³ and R² taken together represent (CH₂)_(n),            (CH₂)_(n)O(CH₂)_(p), (CH₂)_(n)NR^(b)(CH₂)_(p), or            (CH₂)_(n)S(═O)_(m)(CH₂)_(p); and        -   R⁴ is selected from H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl,            heteroaryl, halogen and C₁-C₆ haloalkyl;    -   R⁵ is selected from (a) H, (b) C₁-C₆ alkyl, (c) aryl, (d)        aralkyl, (e) CH(R⁷)OC(═O)R⁸, (f) CH(R⁷)OC(═O)OR⁸, and (g) a        (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl group having the        following formula:

-   -   -   wherein R⁶ is C₁-C₆ alkyl;

    -   R⁷ is hydrogen or C₁-C₆ alkyl;

    -   R⁸ is C₁-C₆ alkyl or C₃-C₆-cycloalkyl;

    -   R^(a) is selected from: (a) H, (b) C₁-C₆ alkyl, (c) halogen, (d)        aryl, (e) OR^(b), (f) cyano, (g) heteroaryl, (h) C₃-C₆        cycloalkyl, and (i) C₁-C₆ haloalkyl;

    -   R^(a′) is selected from: (a) cyano, (b) C₁-C₆ alkyl, (c)        halogen, (d) aryl, (e) OR^(b), (f) heteroaryl, (g) C₃-C₆        cycloalkyl, and (h) C₁-C₆ haloalkyl;

    -   R^(b) and R^(c) are independently selected from: (a) H, (b)        C₁-C₆ alkyl, (c) aryl, (d) heteroaryl, (e) C₃-C₆ cycloalkyl, (f)        C₂-C₆ heterocycle, or (g) C₁-C₆ haloalkyl; or        -   R^(b) and R^(c) taken together with the N to which they are            both attached form a 3- to 6-membered heterocycle optionally            having an additional heteroatom selected from

    -   N, O and S;

    -   m is 0, 1, or 2;

    -   n is 1, 2 or 3; and

    -   p is 1, 2 or 3.

Some embodiments provided herein describe compounds of Formula I:

or a pharmaceutically acceptable salt, solvate, solvate of the salt,hydrate, a single stereoisomer, a mixture of stereoisomers, a racemicmixture of stereoisomers, or prodrug thereof;

wherein

-   -   Ar is an aryl or a heteroaryl, wherein said aryl and said        heteroaryl are each optionally substituted with 1 to 3        substituents independently selected from: (a) C₁-C₆ alkyl, (b)        C₃-C₇ cycloalkyl, (c) heterocycle, (d) aryl, (e) heteroaryl, (f)        halogen, (g) CN, (h) OR^(b), (i) N(R^(b))C(═O)R^(c), (j)        C(═O)N(R^(b))(R^(c)), (k) S(═O)_(m)R^(b), (l)        S(═O)₂N(R^(b))(R^(c)), (m) N(R^(b))S(═O)₂R^(c), (n) SF₅, and (o)        C₁-C₆ haloalkyl;    -   W is selected from: (a) C(═O)OR⁵, (b) C(═O)NHOH, (c)        S(═O)₂NHR^(b), (d) S(═O)₂NHC(═O)R^(b), (e)        NHC(═O)NHSO₂R^(b), (f) 1H-tetrazole, (g)        1,2,4-oxadiazol-5(4H)one, (h) 1,2,4-thiadiazol-5(4H)one, (i)        1,2,4-oxadiazole-5(4H)-thione, (j) 1,2,4-triazole-5(4H)-one, (k)        tetrazol-5(4H)-one, and (l) C(═O)NHS(═O)₂R^(b);    -   X¹, X², X³, X⁴, and X⁵ are each independently N or CR^(a),        wherein not more than 2 of X¹, X², X³, X⁴, and X⁵ are N;    -   Y is selected from: (a) a bond, (b) (CH₂)_(n) wherein 1 to 4        hydrogen atoms may be replaced by R^(a′), (c) O, and (d) NR^(b);    -   Z is (CH₂)_(n), wherein 1 to 4 hydrogen atoms may be replaced by        R^(a′);    -   R¹ and R² are independently selected from: (a) H, (b) C₁-C₆        alkyl, (c) C₃-C₆ cycloalkyl, and (d) C₁-C₆ haloalkyl, wherein R²        is not H; or        -   R¹ and R² taken together represent —(CH₂)_(n)—,            —(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or            —(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—;    -   R³ and R⁴ are independently selected from: (a) H, (b) C₁-C₆        alkyl, (c) C₃-C₆ cycloalkyl, (d) aryl, (e) heteroaryl, (f)        halogen, (g) C₁-C₆ haloalkyl; or        -   R³ and R⁴ taken together represent —(CH₂)_(n)—,            —(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or            —(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—;    -   or R¹, R², R³ and R⁴ above are selected as follows:        -   R¹ is selected from H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and            C₁-C₆ haloalkyl;        -   R³ and R² taken together represent (CH₂)_(n),            (CH₂)_(n)O(CH₂)_(p), (CH₂)_(n)NR^(b)(CH₂)_(p), or            (CH₂)_(n)S(═O)_(m)(CH₂)_(p); and        -   R⁴ is selected from H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl,            heteroaryl, halogen and C₁-C₆ haloalkyl;    -   R⁵ is selected from (a) H, (b) C₁-C₆ alkyl; (c) aryl, (d)        aralkyl, (e) CH(R⁷)OC(═O)R⁸, (f), CH(R⁷)OC(═O)OR⁸, and (g) a        (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl group having the        following formula:

-   -   -   wherein R⁶ is C₁-C₆ alkyl;

    -   R⁷ is hydrogen or C₁-C₆ alkyl;

    -   R⁸ is C₁-C₆ alkyl or C₃-C₆-cycloalkyl;

    -   R^(a) is selected from: (a) H, (b) C₁-C₆ alkyl, (c) halogen, (d)        aryl, (e) OR^(b), (f) cyano, (g) heteroaryl, (h) C₃-C₆        cycloalkyl, and (i) C₁-C₆ haloalkyl;

    -   R^(a′) is selected from: (a) cyano, (b) C₁-C₆ alkyl, (c)        halogen, (d) aryl, (e) OR^(b), (f) heteroaryl, (g) C₃-C₆        cycloalkyl, and (h) C₁-C₆ haloalkyl;

    -   R^(b) and R^(c) are independently selected from: (a) H, (b)        C₁-C₆ alkyl, (c) aryl, (d) heteroaryl,

    -   (e) C₃-C₆ cycloalkyl, or (f) C₁-C₆ haloalkyl; or        -   R^(b) and R^(c) taken together with the N to which they are            both attached form a 3- to 6-membered heterocycle optionally            having an additional heteroatom selected from

    -   N, O and S;

    -   m is 0, 1, or 2;

    -   n is 1, 2 or 3; and

    -   p is 1, 2 or 3.

In some embodiments, Ar is an aryl or a heteroaryl, wherein said aryland said heteroaryl are each optionally substituted with 1 to 3substituents independently selected from the group consisting of:

-   -   (a) C₁-C₆ alkyl,    -   (b) C₃-C₇ cycloalkyl,    -   (c) heterocycle,    -   (d) aryl,    -   (e) heteroaryl,    -   (f) halogen,    -   (g) CN,    -   (h) OR^(b),    -   (i) N(R^(b))C(═O)R^(c),    -   (j) C(═O)N(R^(b))(R^(c)),    -   (k) S(═O)_(m)R^(b),    -   (l) S(═O)₂N(R^(b))(R^(c)),    -   (m) N(R^(b))S(═O)₂R^(c),    -   (n) SF₅ and    -   (o) C₁-C₆ haloalkyl.

In some embodiments, W is selected from the group consisting of:

-   -   (a) CO₂H,    -   (b) C(═O)NHOH,    -   (c) S(═O)₂NHR^(b),    -   (d) S(═O)₂NHC(═O)R^(b),    -   (e) NHC(═O)NHSO₂R^(b),    -   (f) 1H-tetrazole,    -   (g) 1,2,4-oxadiazol-5(4H)one,    -   (h) 1,2,4-thiadiazol-5(4H)one,    -   (i) 1,2,4-oxadiazole-5(4H)-thione,    -   (j) 1,2,4-triazole-5(4H)-one,    -   (k) tetrazol-5(4H)-one, and    -   (l) C(═O)NHS(═O)₂R^(b).

In some embodiments, X¹, X², X³, X⁴, and X⁵ are each independently N orCR^(a), wherein not more than 2 of X¹, X², X³, X⁴, and X⁵ are N.

In some embodiments, Y is selected from: (a) a bond, (b) (CH₂)_(n)wherein 1 to 4 hydrogen atoms may be replaced by R^(a′), (c) O, and (d)NR^(b).

In some embodiments, Z is (CH₂)_(n), wherein 1 to 4 hydrogen atoms maybe replaced by R^(a′).

In some embodiments, R¹ and R² are independently selected from:

-   -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) C₃-C₆ cycloalkyl, and    -   (d) C₁-C₆ haloalkyl.

In some embodiments, R¹ and R² are not both H.

In some embodiments, R¹ and R² taken together represent —(CH₂)_(n)—,—(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or—(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—.

In some embodiments, R³ and R⁴ are independently selected from the groupconsisting of:

-   -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) C₃-C₆ cycloalkyl,    -   (d) aryl,    -   (e) heteroaryl,    -   (f) halogen, and    -   (g) C₁-C₆ haloalkyl.

In some embodiments, R³ and R⁴ taken together represent —(CH₂)_(n)—,—(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or—(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—.

In some embodiments, R³ and R² taken together represent (CH₂)_(n),(CH₂)_(n)O(CH₂)_(p), (CH₂)_(n)NR^(b)(CH₂)_(p), or(CH₂)_(n)S(═O)_(m)(CH₂)_(p).

In some embodiments, R^(a) is selected from the group consisting of:

-   -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) halogen,    -   (d) aryl,    -   (e) OR^(b),    -   (f) cyano,    -   (g) heteroaryl,    -   (h) C₃-C₆ cycloalkyl, and    -   (i) C₁-C₆ haloalkyl.

In some embodiments, R^(a′) is selected from the group consisting of:

-   -   (a) cyano,    -   (b) C₁-C₆ alkyl,    -   (c) halogen,    -   (d) aryl,    -   (e) OR^(b),    -   (f) heteroaryl,    -   (g) C₃-C₆ cycloalkyl, and    -   (h) C₁-C₆ haloalkyl.

In some embodiments, R^(b) and R^(c) are independently selected from thegroup consisting of:

-   -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) aryl,    -   (d) heteroaryl,    -   (e) C₃-C₆ cycloalkyl, and    -   (f) C₁-C₆ haloalkyl.

In some embodiments, R^(b) and R^(c) taken together with the N to whichthey are both attached form a 3- to 6-membered heterocycle optionallyhaving an additional heteroatom selected from N, O and S.

In some embodiments, m is 0, 1, or 2.

In some embodiments, n is 1, 2 or 3.

In some embodiments, p is 1, 2 or 3.

In some embodiments, Ar is phenyl optionally substituted with 1 to 3substituents independently selected from:

-   -   (a) halogen,    -   (b) cyano,    -   (c) C₁-C₆ alkyl,    -   (d) SF₅,    -   (e) C₁-C₆ haloalkyl,    -   (f) OR^(b) wherein R^(b) is C₁-C₆ alkyl, aryl, heteroaryl, C₃-C₆        cycloalkyl or C₁-C₆ haloalkyl,    -   (g) heterocycle,    -   (h) aryl, and    -   (i) heteroaryl.

In some embodiments, Ar is phenyl optionally substituted with 1 to 3substituents independently selected from:

-   -   (a) halogen,    -   (b) cyano,    -   (c) C₁-C₆ alkyl,    -   (d) SF₅, and    -   (e) C₁-C₆ haloalkyl.

In some embodiments, each of X¹, X², X³, X⁴ and X⁵ is independentlyC—R^(a). In some embodiments, one of X¹, X², X³, X⁴ and X⁵ is N, and theothers are each independently C—R^(a). In some embodiments, each of X¹,X², X³, X⁴ and X⁵ is independently C—R^(a). In some embodiments, R^(a)is H or a halogen atom.

In some embodiments, W is selected from the group consisting of: (a)CO₂H and (b) 1H-tetrazole.

In some embodiments, Z is —CH₂—.

In some embodiments, Y is a bond or —CH₂—.

In some embodiments, R¹ and R² taken together represent —CH₂— or—CH₂CH₂—.

In some embodiments, Y is —CH₂—, and R³ and R² taken together represent—CH₂— or —CH₂CH₂—.

Some embodiments provided herein describe a compound of Formula I havingthe structure of Formula Ia:

or a pharmaceutically acceptable salt, solvate, solvate of the salt,hydrate, a single stereoisomer, a mixture of stereoisomers, a racemicmixture of stereoisomers, or prodrug thereof.

In some embodiments, Ar is phenyl optionally substituted with 1 to 3substituents independently selected from:

-   -   (a) halogen,    -   (b) cyano,    -   (c) C₁-C₆ alkyl,    -   (d) SF₅,    -   (e) C₁-C₆ haloalkyl,    -   (f) OR^(b) wherein R^(b) is C₁-C₆ alkyl, aryl, heteroaryl, C₃-C₆        cycloalkyl or C₁-C₆ haloalkyl,    -   (g) heterocycle,    -   (h) aryl, and    -   (i) heteroaryl.

In some embodiments, Ar is phenyl optionally substituted with 1 to 3substituents independently selected from:

-   -   (a) halogen,    -   (b) cyano,    -   (c) C₁-C₆ alkyl,    -   (d) SF₅, and    -   (e) C₁-C₆ haloalkyl.

In some embodiments, each X¹, X², X³, X⁴ and X⁵ is independentlyC—R^(a). In some embodiments, one of X¹, X², X³, X⁴ and X⁵ is N, and theothers are each independently C—R^(a).

In some embodiments, W is selected from the group consisting of: (a)CO₂H and (b) 1H-tetrazole.

In some embodiments, Y is a bond or —CH₂—.

In some embodiments, n is 1 or 2.

In some embodiments, R³ and R⁴ are independently selected from the groupconsisting of: (a) H, (b) C₁-C₃ alkyl, and (c) C₁-C₃ haloalkyl.

In some embodiments, R^(a) is selected from the group consisting of Hand halogen.

In some embodiments, Y is a bond, and n is 1.

Some embodiments provided herein describe a compound of Formula I havingthe structure of Formula Ib:

-   or a pharmaceutically acceptable salt, solvate, solvate of the salt,    hydrate, a single stereoisomer, a mixture of stereoisomers, a    racemic mixture of stereoisomers, or prodrug thereof.

In some embodiments, Ar is phenyl optionally substituted with 1 to 3substituents independently selected from:

-   -   (a) halogen,    -   (b) cyano,    -   (c) C₁-C₆ alkyl,    -   (d) SF₅,    -   (e) C₁-C₆ haloalkyl,    -   (f) OR^(b) wherein R^(b) is C₁-C₆ alkyl, aryl, heteroaryl, C₃-C₆        cycloalkyl or C₁-C₆ haloalkyl,    -   (g) heterocycle,    -   (h) aryl, and    -   (i) heteroaryl.

In some embodiments, Ar is phenyl optionally substituted with 1 to 3substituents independently selected from:

-   -   (a) halogen,    -   (b) cyano,    -   (c) C₁-C₆ alkyl,    -   (d) SF₅, and    -   (e) C₁-C₆ haloalkyl.

In some embodiments, each X¹, X², X³, X⁴ and X⁵ is independentlyC—R^(a), or one of X¹, X², X³, X⁴ and X⁵ is N, and the others are eachindependently C—R^(a).

In some embodiments, W is selected from the group consisting of: (a)CO₂H and (b) 1H-tetrazole.

In some embodiments, n is 1 or 2.

In some embodiments, R⁴ is selected from the group consisting of: (a) H,(b) C₁-C₃, and

-   -   (c) C₁-C₃ haloalkyl.

In some embodiments, R^(a) is selected from the group consisting of Hand halogen.

In some embodiments, n is 1.

Some embodiments provided herein describe a compound of Formula I havingthe Formula Ic or Id:

-   or a pharmaceutically acceptable salt, solvate, solvate of the salt,    hydrate, a single stereoisomer, a mixture of stereoisomers, a    racemic mixture of stereoisomers, or prodrug thereof.

In some embodiments, each X¹, X², X³, X⁴ and X⁵ is independentlyC—R^(a).

In some embodiments, one of X¹, X², X³, X⁴ and X⁵ is N, and the othersare each independently C—R^(a).

In some embodiments, R^(a) is selected from the group consisting of Hand halogen.

In some embodiments, R^(d) is selected from:

-   -   (a) CN,    -   (b) C₁-C₃ alkyl,    -   (c) SF₅,    -   (d) C₁-C₃ haloalkyl,    -   (e) OR^(b) wherein R^(b) is C₁-C₆ alkyl, aryl, heteroaryl, C₃-C₆        cycloalkyl or C₁-C₆ haloalkyl,    -   (f) heterocycle,    -   (g) aryl, and    -   (h) heteroaryl.

In some embodiments, R^(d) is selected from the group consisting of: (a)CN, (b) C₁-C₃ alkyl, (c) SF₅, and (d) C₁-C₃ haloalkyl.

In some embodiments, each X¹, X², X³, X⁴ and X⁵ is CH; or one of X¹, X²,X³, X⁴ and X⁵ is C—R^(a) and the others are CH, and R^(a) is halogen.

In some embodiments, the compound is selected from:

-   2-(3-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   2-(3-(1-((4-(trifluoromethyl)phenyl)methyl-d₂)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   6-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (5)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (5)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (5)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   6-(1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   6-(1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (5)-6-(1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   3-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)propanoic    acid;-   3-(3-methyl-3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)cyclobutyl)propanoic    acid;-   cis-3-(3-methyl-3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)cyclobutyl)propanoic    acid;-   N-(3-(2-oxo-2-(phenylsulfonamido)ethyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide;-   N-(3-((3-(phenylsulfonyl)ureido)methyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide;-   N-(3-((1H-tetrazol-5-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide;-   2-(4-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[2.1.1]hexan-1-yl)acetic    acid;-   6-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   6-(5-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(5-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(5-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   6-(5-chloro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(5-chloro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(5-chloro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   6-(6-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(6-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(6-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   6-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   6-(1-(4-(difluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-(difluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(1-(4-(difluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   2-(4-(1-(4-(difluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[2.1.1]hexan-1-yl)acetic    acid;-   2-(3-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   2-(4-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[2.1.1]hexan-1-yl)acetic    acid;-   2-(4-(1-((4-(pentafluorothiol)phenyl)methyl)-1H-indole-7-carboxamido)bicyclo[2.1.1]hexan-1-yl)acetic    acid;-   6-(1-((4-(pentafluorothiol)phenyl)methyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-((4-(pentafluorothiol)phenyl)methyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(1-((4-(pentafluorothiol)phenyl)methyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   6-(1-(4-(difluoromethyl)benzyl)-4-fluoro-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-(difluoromethyl)benzyl)-4-fluoro-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (5)-6-(1-(4-(difluoromethyl)benzyl)-4-fluoro-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   2-(3-(1-(4-(difluoromethyl)benzyl)-4-fluoro-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   2-(3-(5-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   2-(3-(1-([1,1′-biphenyl]-4-ylmethyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]    pentan-1-yl)acetic acid;-   2-(3-(1-([1,1′-biphenyl]-4-ylmethyl)-4-fluoro-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   2-(3-(1-([1,1′-biphenyl]-4-ylmethyl)-1H-indazole-7-carboxamido)bicyclo[1.1.1]    pentan-1-yl)acetic acid;-   2-(3-(1-(4-(trifluoromethoxy)benzyl)-1H-indazole-7-carboxamido)bicyclo[1.1.1]    pentan-1-yl)acetic acid;-   2-(3-(4-fluoro-1-(4-iodobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)    acetic acid;-   2-(3-(4-fluoro-1-(4-(pyridine-4-yl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)    acetic acid; and-   2-(3-(4-fluoro-1-(4-morpholinobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)    acetic acid;    or a pharmaceutically acceptable salt, solvate, solvate of the salt,    hydrate, a single stereoisomer, a mixture of stereoisomers, a    racemic mixture of stereoisomers, or prodrug thereof.

Some embodiments provided herein describe pharmaceutical compositionscomprising a compound of any of Formula I, Ia, Ib, Ic, or Id, or apharmaceutically acceptable salt, solvate, solvate of the salt, hydrate,a single stereoisomer, a mixture of stereoisomers, a racemic mixture ofstereoisomers, or prodrug thereof of any of the foregoing, and apharmaceutically acceptable carrier.

Some embodiments provided herein describe methods for the treatment ofcancer comprising administering to a patient in need thereof a compoundof any of Formula I, Ia, Ib, Ic, or Id, or a pharmaceutically acceptablesalt, solvate, solvate of the salt, hydrate, a single stereoisomer, amixture of stereoisomers, a racemic mixture of stereoisomers, or prodrugthereof of any of the foregoing, or a pharmaceutical compositioncomprising any of Formula I, Ia, Ib, Ic, or Id, or a pharmaceuticallyacceptable salt of any of the foregoing.

In some embodiments, the cancer is selected from the group consisting ofglioblastoma, bone cancer, head and neck cancer, melanoma, basal cellcarcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer,esophageal cancer, gastric cancer, intestinal cancer, colon cancer,bladder cancer, hepatocellular carcinoma, renal cell carcinoma,pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breastcancer, and prostate cancer.

In some embodiments, the treatment further comprises an additional agentselected from an anti-PD-1 antibody and an anti-PD-L1 antibody.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B illustrate the effect of Compound A on tumor volume in amurine colon cancer model.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein in some embodiments are selective EP4 receptorantagonists and compositions comprising these compounds (i.e., theselective EP4 receptor antagonists). The compounds and compositions areuseful for the treatment of cancer.

Some embodiments provided herein describe compounds of Formula I:

or a pharmaceutically acceptable salt, solvate, solvate of the salt, orprodrug thereof.

In certain embodiments, provided herein are compounds of Formula I:

or a pharmaceutically acceptable salt, solvate, solvate of the salt, orprodrug thereof, wherein:

-   -   Ar is an aryl or a heteroaryl, wherein said aryl and said        heteroaryl are each optionally substituted with 1 to 3        substituents independently selected from the group consisting        of:    -   (a) C₁-C₆ alkyl,    -   (b) C₃-C₇ cycloalkyl,    -   (c) heterocycle,    -   (d) aryl,    -   (e) heteroaryl,    -   (f) halogen,    -   (g) CN,    -   (h) OR^(b),    -   (i) N(R^(b))C(═O)R^(c),    -   (j) C(═O)N(R^(b))(R^(c)),    -   (k) S(═O)_(m)R^(b),    -   (l) S(═O)₂N(R^(b))(R^(c)),    -   (m) N(R^(b))S(═O)₂R^(c),    -   (n) SF₅; and    -   (o) C₁-C₆ haloalkyl.

-   W is selected from the group consisting of:    -   (a) CO₂H,    -   (b) C(═O)NHOH,    -   (c) S(═O)₂NHR^(b),    -   (d) S(═O)₂NHC(═O)R^(b),    -   (e) NHC(═O)NHSO₂R^(b),    -   (f) 1H-tetrazole,    -   (g) 1,2,4-oxadiazol-5(4H)one,    -   (h) 1,2,4-thiadiazol-5(4H)one,    -   (i) 1,2,4-oxadiazole-5(4H)-thione,    -   (j) 1,2,4-triazole-5(4H)-one,    -   (k) tetrazol-5(4H)-one, and    -   (l) C(═O)NHS(═O)₂R^(b);

-   X¹, X², X³, X⁴, and X⁵ are each independently N or CR^(a), wherein    not more than 2 of X¹, X², X³, X⁴, and X⁵ are N;

-   Y is selected from:    -   (a) a bond,    -   (b) (CH₂)_(n) wherein 1 to 4 hydrogen atoms may be replaced by        R^(a′),    -   (c) O, and    -   (d) NR^(b);

-   Z is (CH₂)_(n), wherein 1 to 4 hydrogen atoms may be replaced by    R^(a′);

-   R¹ and R² are independently selected from:    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) C₃-C₆ cycloalkyl, and    -   (d) C₁-C₆ haloalkyl;    -   wherein R¹ and R² are not both H; or

-   R¹ and R² taken together represent —(CH₂)_(n)—,    —(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or    —(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—;

-   R³ and R⁴ are independently selected from the group consisting of:    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) C₃-C₆ cycloalkyl,    -   (d) aryl,    -   (e) heteroaryl,    -   (f) halogen,    -   (g) C₁-C₆ haloalkyl; or

-   R³ and R⁴ taken together represent —(CH₂)_(n)—,    —(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or    —(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—; or

-   R³ and R² taken together represent (CH₂)_(n), (CH₂)_(n)O(CH₂)_(p),    (CH₂)_(n)NR^(b)(CH₂)_(p), or (CH₂)_(n)S(═O)_(m)(CH₂)_(p);

-   R^(a) is selected from the group consisting of:    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) halogen,    -   (d) aryl,    -   (e) OR^(b),    -   (f) cyano,    -   (g) heteroaryl,    -   (h) C₃-C₆ cycloalkyl,    -   (i) C₁-C₆ haloalkyl;

-   R^(a′) is selected from the group consisting of:    -   (a) cyano,    -   (b) C₁-C₆ alkyl,    -   (c) halogen,    -   (d) aryl,    -   (e) OR^(b),    -   (f) heteroaryl,    -   (g) C₃-C₆ cycloalkyl, and    -   (h) C₁-C₆ haloalkyl;

-   R^(b) and R^(c) are independently selected from the group consisting    of    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) aryl,    -   (d) heteroaryl,    -   (e) C₃-C₆ cycloalkyl,    -   (f) C₂-C₆ heterocycle and    -   (g) C₁-C₆ haloalkyl; or

-   R^(b) and R^(c) taken together with the N to which they are both    attached form a 3- to 6-membered heterocycle optionally having an    additional heteroatom selected from N, O and S;

-   m is 0, 1, or 2;

-   n is 1, 2 or 3; and

-   p is 1, 2 or 3.

In certain embodiments, provided herein are compounds of Formula I:

or a pharmaceutically acceptable salt, solvate, solvate of the salt, orprodrug thereof, wherein:

-   -   Ar is an aryl or a heteroaryl, wherein said aryl and said        heteroaryl are each optionally substituted with 1 to 3        substituents independently selected from the group consisting        of:    -   (a) C₁-C₆ alkyl,    -   (b) C₃-C₇ cycloalkyl,    -   (c) heterocycle,    -   (d) aryl,    -   (e) heteroaryl,    -   (f) halogen,    -   (g) CN,    -   (h) OR^(b),    -   (i) N(R^(b))C(═O)R^(c),    -   (j) C(═O)N(R^(b))(R^(c)),    -   (k) S(═O)_(m)R^(b),    -   (l) S(═O)₂N(R^(b))(R^(c)),    -   (m) N(R^(b))S(═O)₂R^(c),    -   (n) SF₅; and    -   (o) C₁-C₆ haloalkyl.

-   W is selected from the group consisting of:    -   (a) CO₂H,    -   (b) C(═O)NHOH,    -   (c) S(═O)₂NHR^(b),    -   (d) S(═O)₂NHC(═O)R^(b),    -   (e) NHC(═O)NHSO₂R^(b),    -   (f) 1H-tetrazole,    -   (g) 1,2,4-oxadiazol-5(4H)one,    -   (h) 1,2,4-thiadiazol-5(4H)one,    -   (i) 1,2,4-oxadiazole-5(4H)-thione,    -   (j) 1,2,4-triazole-5(4H)-one,    -   (k) tetrazol-5(4H)-one, and    -   (l) C(═O)NHS(═O)₂R^(b);

-   X¹, X², X³, X⁴, and X⁵ are each independently N or CR^(a), wherein    not more than 2 of X¹, X², X³, X⁴, and X⁵ are N;

-   Y is selected from:    -   (a) a bond,    -   (b) (CH₂)_(n) wherein 1 to 4 hydrogen atoms may be replaced by        R^(a′),    -   (c) O, and    -   (d) NR^(b);

-   Z is (CH₂)_(n), wherein 1 to 4 hydrogen atoms may be replaced by    R^(a′);

-   R¹ and R² are independently selected from:    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) C₃-C₆ cycloalkyl, and    -   (d) C₁-C₆ haloalkyl;    -   wherein R¹ and R² are not both H; or

-   R¹ and R² taken together represent —(CH₂)_(n)—,    —(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or    —(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—;

-   R³ and R⁴ are independently selected from the group consisting of:    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) C₃-C₆ cycloalkyl,    -   (d) aryl,    -   (e) heteroaryl,    -   (f) halogen,    -   (g) C₁-C₆ haloalkyl; or

-   R³ and R⁴ taken together represent —(CH₂)_(n)—,    —(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or    —(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—; or

-   R³ and R² taken together represent (CH₂)_(n), (CH₂)_(n)O(CH₂)_(p),    (CH₂)_(n)NR^(b)(CH₂)_(p), or (CH₂)_(n)S(═O)_(m)(CH₂)_(p);

-   R^(a) is selected from the group consisting of:    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) halogen,    -   (d) aryl,    -   (e) OR^(b),    -   (f) cyano,    -   (g) heteroaryl,    -   (h) C₃-C₆ cycloalkyl,    -   (i) C₁-C₆ haloalkyl;

-   R^(a′) is selected from the group consisting of:    -   (a) cyano,    -   (b) C₁-C₆ alkyl,    -   (c) halogen,    -   (d) aryl,    -   (e) OR^(b),    -   (f) heteroaryl,    -   (g) C₃-C₆ cycloalkyl, and    -   (h) C₁-C₆ haloalkyl;

-   R^(b) and R^(c) are independently selected from the group consisting    of    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) aryl,    -   (d) heteroaryl,    -   (e) C₃-C₆ cycloalkyl, and    -   (f) C₁-C₆ haloalkyl; or

-   R^(b) and R^(c) taken together with the N to which they are both    attached form a 3- to 6-membered heterocycle optionally having an    additional heteroatom selected from N, O and S;

-   m is 0, 1, or 2;

-   n is 1, 2 or 3; and

-   p is 1, 2 or 3.

In some embodiments, Ar is an aryl or a heteroaryl, wherein said aryland said heteroaryl are each optionally substituted with 1 to 3substituents independently selected from the group consisting of:

-   -   (a) C₁-C₆ alkyl,    -   (b) C₃-C₇ cycloalkyl,    -   (c) heterocycle,    -   (d) aryl,    -   (e) heteroaryl,    -   (f) halogen,    -   (g) CN,    -   (h) OR^(b),    -   (i) N(R^(b))C(═O)R^(c),    -   (j) C(═O)N(R^(b))(R^(c)),    -   (k) S(═O)_(m)R^(b),    -   (l) S(═O)₂N(R^(b))(R^(c)),    -   (m) N(R^(b))S(═O)₂R^(c),    -   (n) SF₅, and    -   (o) C₁-C₆ haloalkyl.

In some embodiments, Ar is a mono-substituted phenyl group. In someembodiments, Ar is a di-substituted phenyl group. In some embodiments,Ar is a tri-substituted phenyl group. In some embodiments, Ar is amono-substituted pyridyl group. In some embodiments, Ar is amono-substituted pyrimidinyl group. In some embodiments, Ar is adi-substituted pyridyl group. In some embodiments, Ar is adi-substituted pyrimidinyl group. In some embodiments, themono-substituted group is substituted with CN (cyano), halogen, CF₃,CF₂H, SF₅, or an unsubstituted C₁-C₆ alkyl. In some embodiments, themono-substituted group is substituted with CN (cyano), halogen,haloalkyl, aryl, heteroaryl, haloalkoxy, heterocycle, or alkyl. In someembodiments, the mono-substituted group is substituted with CN (cyano),halogen, haloalkyl, phenyl, pyridyl, haloalkoxy, or heterocycle. In someembodiments, Ar is a phenyl substituted with one to three substituentsselected from aryl, heteroaryl, cycloalkyl, heterocycle, CN (cyano),halogen, haloalkyl, SF₅, —OR^(b), and alkyl; and each R^(b) isindependently H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, heterocyclyl, or C₁-C₆haloalkyl.

In some embodiments, W is selected from the group consisting of:

-   -   (a) CO₂H,    -   (b) C(═O)NHOH,    -   (c) S(═O)₂NHR^(b),    -   (d) S(═O)₂NHC(═O)R^(b),    -   (e) NHC(═O)NHSO₂R^(b),    -   (f) 1H-tetrazole,    -   (g) 1,2,4-oxadiazol-5(4H)one,    -   (h) 1,2,4-thiadiazol-5(4H)one,    -   (i) 1,2,4-oxadiazole-5(4H)-thione,    -   (j) 1,2,4-triazole-5(4H)-one,    -   (k) tetrazol-5(4H)-one, and    -   (l) C(═O)NHS(═O)₂R^(b).

In some embodiments, X¹, X², X³, X⁴, and X⁵ are each independently N orCR^(a), with the proviso that not more than 2 of X¹, X², X³, X⁴, and X⁵are N.

In some embodiments, Y is selected from:

-   -   (a) a bond,    -   (b) (CH₂)_(n) wherein 1 to 4 hydrogen atoms may be replaced by        R^(a′),    -   (c) O, and    -   (d) NR^(b).

In some embodiments, Z is (CH₂)_(n), wherein 1 to 4 hydrogen atoms maybe replaced by R^(a′).

In some embodiments, R¹ and R² are independently selected from:

-   -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) C₃-C₆ cycloalkyl, and    -   (d) C₁-C₆ haloalkyl.

In some embodiments, R¹ and R² are not both H.

In some embodiments, R¹ and R² taken together represent —(CH₂)_(n)—,—(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or—(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—.

In some embodiments, R³ and R⁴ are independently selected from the groupconsisting of:

-   -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) C₃-C₆ cycloalkyl,    -   (d) aryl,    -   (e) heteroaryl,    -   (f) halogen, and    -   (g) C₁-C₆ haloalkyl.

In some embodiments, R³ and R⁴ taken together represent —(CH₂)_(n)—,—(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or—(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—.

In some embodiments, R³ and R² taken together represent (CH₂)_(n),(CH₂)_(n)O(CH₂)_(p), (CH₂)_(n)NR^(b)(CH₂)_(p), or(CH₂)_(n)S(═O)_(m)(CH₂)_(p).

In some embodiments, R^(a) is selected from the group consisting of:

-   -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) halogen,    -   (d) aryl,    -   (e) OR^(b),    -   (f) cyano,    -   (g) heteroaryl,    -   (h) C₃-C₆ cycloalkyl, and    -   (i) C₁-C₆ haloalkyl.

In some embodiments, R^(a′) is selected from the group consisting of:

-   -   (a) cyano,    -   (b) C₁-C₆ alkyl,    -   (c) halogen,    -   (d) aryl,    -   (e) OR^(b),    -   (f) heteroaryl,    -   (g) C₃-C₆ cycloalkyl, and    -   (h) C₁-C₆ haloalkyl.

In some embodiments, R^(b) and R^(c) are independently selected from thegroup consisting of:

-   -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) aryl,    -   (d) heteroaryl,    -   (e) C₃-C₆ cycloalkyl, and    -   (f) C₁-C₆ haloalkyl.

In some embodiments, R^(b) and R^(c) taken together with the N to whichthey are both attached form a 3- to 6-membered heterocycle optionallyhaving an additional heteroatom selected from N, O and S.

In some embodiments, m is 0, 1, or 2.

In some embodiments, n is 1, 2 or 3.

In some embodiments, p is 1, 2 or 3.

In some embodiments, Ar is phenyl optionally substituted with 1 to 3substituents independently selected from:

-   -   (a) halogen,    -   (b) cyano,    -   (c) C₁-C₆ alkyl,    -   (d) SF₅,    -   (e) C₁-C₆ haloalkyl    -   (f) OR^(b) wherein R^(b) is C₁-C₆ alkyl, aryl, heteroaryl, C₃-C₆        cycloalkyl or C₁-C₆ haloalkyl;    -   (g) heterocycle,    -   (h) aryl, and    -   (i) heteroaryl.

In some embodiments, Ar is phenyl optionally substituted with 1 to 3substituents independently selected from:

-   -   (a) halogen,    -   (b) cyano,    -   (c) C₁-C₆ alkyl,    -   (d) SF₅, and    -   (e) C₁-C₆ haloalkyl.

In some embodiments, each of X¹, X², X³, X⁴ and X⁵ is independentlyC—R^(a), or one of X¹, X², X³, X⁴ and X⁵ is N, and the others are eachindependently C—R^(a).

In some embodiments, each of X¹, X², X³, X⁴ and X⁵ is independentlyC—R^(a).

In some embodiments, R^(a) is H or a halogen atom.

In some embodiments, W is selected from the group consisting of:

-   -   (a) CO₂H and    -   (b) 1H-tetrazole.

In some embodiments, Z is —CH₂—.

In some embodiments, Y is a bond or —CH₂—.

In some embodiments, R¹ and R² taken together represent —CH₂—, —CH₂CH₂—or —CH₂CH₂CH₂—. In some embodiments, R¹ and R² taken together represent—CH₂— or —CH₂CH₂—.

In some embodiments, Y is a direct bond or —CH₂—, and R³ and R² takentogether represent —CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂—.

In some embodiments, Y is —CH₂—, and R³ and R² taken together represent—CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂—.

In some embodiments, Y is —CH₂—, and R³ and R² taken together represent—CH₂— or —CH₂CH₂—.

Some embodiments provide compounds having the Formula Ia:

or a pharmaceutically acceptable salt, solvate, solvate of the salt, orprodrug thereof.

In some embodiments, Ar is aryl or heteroaryl optionally substitutedwith 1 to 3 substituents independently selected from:

-   -   (a) halogen,    -   (b) cyano,    -   (c) C₁-C₆ alkyl,    -   (d) SF₅,    -   (e) C₁-C₆ haloalkyl,    -   (f) OR^(b) wherein R^(b) is C₁-C₆ alkyl, aryl, heteroaryl, C₃-C₆        cycloalkyl or C₁-C₆ haloalkyl,    -   (g) heterocycle,    -   (h) aryl, and    -   (i) heteroaryl.

In some embodiments, Ar is phenyl optionally substituted with 1 to 3substituents independently selected from:

-   -   (a) halogen,    -   (b) cyano,    -   (c) C₁-C₆ alkyl,    -   (d) SF₅,    -   (e) C₁-C₆ haloalkyl,    -   (f) OR^(b) wherein R^(b) is C₁-C₆ alkyl, aryl, heteroaryl, C₃-C₆        cycloalkyl or C₁-C₆ haloalkyl;    -   (g) heterocycle,    -   (h) aryl, and    -   (i) heteroaryl.

In some embodiments, Ar is phenyl optionally substituted with 1 to 3substituents independently selected from:

-   -   (a) halogen,    -   (b) cyano,    -   (c) C₁-C₆ alkyl,    -   (d) SF₅, and    -   (e) C₁-C₆ haloalkyl.

In some embodiments, each X¹, X², X³, X⁴ and X⁵ is independentlyC—R^(a), or one of X¹, X², X³, X⁴ and X⁵ is N, and the others are eachindependently C—R^(a).

In some embodiments, W is selected from the group consisting of: (a)CO₂H and (b) 1H-tetrazole.

In some embodiments, Y is a bond or —CH₂—.

In some embodiments, n is 1 or 2.

In some embodiments, R³ and R⁴ are independently selected from the groupconsisting of: (a) H, (b) C₁-C₃ alkyl, (c) C₁-C₃ haloalkyl.

In some embodiments, R^(a) is selected from the group consisting of: (a)H and (b) halogen.

In some embodiments, Y is a bond, and n is 1.

Some embodiments provide compounds having the Formula Ib:

or a pharmaceutically acceptable salt, solvate, solvate of the salt, orprodrug thereof.

In some embodiments, Ar is aryl or heteroaryl optionally substitutedwith 1 to 3 substituents independently selected from:

-   -   (a) halogen,    -   (b) cyano,    -   (c) C₁-C₆ alkyl;    -   (d) SF₅,    -   (e) C₁-C₆ haloalkyl,    -   (f) OR^(b) wherein R^(b) is C₁-C₆ alkyl, aryl, heteroaryl, C₃-C₆        cycloalkyl or C₁-C₆ haloalkyl,    -   (g) heterocycle,    -   (h) aryl, and    -   (i) heteroaryl.

In some embodiments, Ar is phenyl optionally substituted with 1 to 3substituents independently selected from:

-   -   (a) halogen,    -   (b) cyano,    -   (c) C₁-C₆ alkyl,    -   (d) SF₅,    -   (e) C₁-C₆ haloalkyl,    -   (f) OR^(b) wherein R^(b) is C₁-C₆ alkyl, aryl, heteroaryl, C₃-C₆        cycloalkyl or C₁-C₆ haloalkyl,    -   (g) heterocycle,    -   (h) aryl, and    -   (i) heteroaryl.

In some embodiments, Ar is phenyl optionally substituted with 1 to 3substituents independently selected from:

-   -   (a) halogen,    -   (b) cyano,    -   (c) C₁-C₆ alkyl,    -   (d) SF₅, and    -   (e) C₁-C₆ haloalkyl.

In some embodiments, each X¹, X², X³, X⁴ and X⁵ is independentlyC—R^(a), or one of X¹, X², X³, X⁴ and X⁵ is N, and the others are eachindependently C—R^(a).

In some embodiments, W is selected from the group consisting of: (a)CO₂H and (b) 1H-tetrazole.

In some embodiments, n is 1 or 2.

In some embodiments, R⁴ is selected from the group consisting of: (a) H,(b) C₁-C₃ alkyl, and (c) C₁-C₃ haloalkyl.

In some embodiments, n is 1 and R^(a) is selected from the groupconsisting of: (a) H and (b) halogen.

Some embodiments provided herein describe compounds of Formula I havingthe structure of Formula Ic or Id:

or a pharmaceutically acceptable salt, solvate, solvate of the salt, orprodrug thereof.

In some embodiments, each X¹, X², X³, X⁴ and X⁵ is independentlyC—R^(a), or one of X¹, X², X³, X⁴ and X⁵ is N, and the others are eachindependently C—R^(a).

In some embodiments, R^(a) is selected from the group consisting of: (a)H and (b) halogen.

In some embodiments, R^(d) is selected from the group consisting of:

-   -   (a) CN,    -   (b) C₁-C₃ alkyl,    -   (c) SF₅, and    -   (d) C₁-C₃ haloalkyl,    -   (e) OR^(b) wherein R^(b) is C₁-C₆ alkyl, aryl, heteroaryl, C₃-C₆        cycloalkyl or C₁-C₆ haloalkyl,    -   (f) heterocycle,    -   (g) aryl, and    -   (h) heteroaryl.

In some embodiments, R^(d) is selected from the group consisting of:

-   -   (a) CN,    -   (b) C₁-C₃ alkyl,    -   (c) SF₅, and    -   (d) C₁-C₃ haloalkyl.

In some embodiments, each X¹, X², X³, X⁴ and X⁵ is CH; or one of X¹, X²,X³, X⁴ and X⁵ is C—R^(a) and the others are CH, and R^(a) is halogen.

In some embodiments, R¹ and R², taken together, represent CH₂, Ar is amono-substituted aryl group, and Y is a bond. In some embodiments, eachX¹, X², X³, X⁴ and X⁵ is CH, R¹ and R², taken together, represent CH₂,Ar is a mono-substituted aryl group, and Y is a bond. In someembodiments, one of X¹, X², X³, X⁴ and X⁵ is C—R^(a) and the others areCH, R^(a) is halogen, R¹ and R², taken together, represent CH₂, Ar is amono-substituted aryl group, and Y is a bond. In some embodiments, oneof X¹, X², X³, X⁴ and X⁵ is N and the others are CH, R¹ and R², takentogether, represent CH₂, Ar is a mono-substituted aryl group, and Y is abond. In some embodiments, two of X¹, X², X³, X⁴ and X⁵ is N and theothers are CH, R¹ and R², taken together, represent CH₂, Ar is amono-substituted aryl group, and Y is a bond.

In certain embodiments, the mono-substituted aryl group is substitutedwith phenyl, pyridyl, heterocycle, CN (cyano), halogen, C₁-C₆ haloalkyl,SF₅, or haloalkoxy.

In certain embodiments, provided herein are compounds of Formula I:

-   -   or a pharmaceutically acceptable salt, solvate, solvate of the        salt, hydrate, a single stereoisomer, a mixture of        stereoisomers, a racemic mixture of stereoisomers, or prodrug        thereof, wherein:    -   Ar is an aryl or a heteroaryl, wherein said aryl and said        heteroaryl are each optionally substituted with 1 to 3        substituents independently selected from:    -   (a) C₁-C₆ alkyl,    -   (b) C₃-C₇ cycloalkyl,    -   (c) heterocycle,    -   (d) aryl,    -   (e) heteroaryl,    -   (f) halogen,    -   (g) CN,    -   (h) OR^(b),    -   (i) N(R^(b))C(═O)R^(c),    -   (j) C(═O)N(R^(b))(R^(c)),    -   (k) S(═O)_(m)R^(b),    -   (l) S(═O)₂N(R^(b))(R^(c)),    -   (m) N(R^(b))S(═O)₂R^(c),    -   (n) SF₅; and    -   (o) C₁-C₆ haloalkyl

-   W is selected from:    -   (a) C(═O)OR⁵,    -   (b) C(═O)NHOH,    -   (c) S(═O)₂NHR^(b),    -   (d) S(═O)₂NHC(═O)R^(b),    -   (e) NHC(═O)NHSO₂R^(b),    -   (f) 1H-tetrazole,    -   (g) 1,2,4-oxadiazol-5(4H)one,    -   (h) 1,2,4-thiadiazol-5(4H)one,    -   (i) 1,2,4-oxadiazole-5(4H)-thione,    -   (j) 1,2,4-triazole-5(4H)-one,    -   (k) tetrazol-5(4H)-one, and    -   (l) C(═O)NHS(═O)₂R^(b);

-   X¹, X², X³, X⁴, and X⁵ are each independently N or CR^(a), wherein    not more than 2 of X¹, X², X³, X⁴, and X⁵ are N;

-   Y is selected from:    -   (a) a bond,    -   (b) (CH₂)_(n) wherein 1 to 4 hydrogen atoms may be replaced by        R^(a′),    -   (c) O, and    -   (d) NR^(b);

-   Z is (CH₂)_(n), wherein 1 to 4 hydrogen atoms may be replaced by    R^(a′);

-   R¹ and R² are independently selected from:    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) C₃-C₆ cycloalkyl, and    -   (d) C₁-C₆ haloalkyl;    -   wherein R² is not H; or

-   R¹ and R² taken together represent —(CH₂)_(n)—,    —(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or    —(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—;

-   R³ and R⁴ are independently selected from:    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) C₃-C₆ cycloalkyl,    -   (d) aryl,    -   (e) heteroaryl,    -   (f) halogen, and    -   (g) C₁-C₆ haloalkyl; or

-   R³ and R⁴ taken together represent —(CH₂)_(n)—,    —(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or    —(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—;

-   or R¹, R², R³ and R⁴ above are selected as follows:

-   R¹ is selected from H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and C₁-C₆    haloalkyl;

-   R³ and R² taken together represent (CH₂)_(n), (CH₂)_(n)O(CH₂)_(p),    (CH₂)_(n)NR^(b)(CH₂)_(p), or (CH₂)_(n)S(═O)_(m)(CH₂)_(p); and

-   R⁴ is selected from H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl,    heteroaryl, halogen and C₁-C₆ haloalkyl;

-   R⁵ is selected from    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) aryl,    -   (d) aralkyl,    -   (e) CH(R⁷)OC(═O)R⁸,    -   (f) CH(R⁷)OC(═O)OR⁸, and    -   (g) a (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl group having the        following formula:

-   -   -   wherein R⁶ is C₁-C₆ alkyl;

-   R⁷ is hydrogen or C₁-C₆ alkyl;

-   R⁸ is C₁-C₆ alkyl or C₃-C₆-cycloalkyl;

-   each R^(a) is independently selected from:    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) halogen,    -   (d) aryl,    -   (e) OR^(b),    -   (f) cyano,    -   (g) heteroaryl,    -   (h) C₃-C₆ cycloalkyl, and    -   (i) C₁-C₆ haloalkyl;

-   each R^(a′) is independently selected from:    -   (a) cyano,    -   (b) C₁-C₆ alkyl,    -   (c) halogen,    -   (d) aryl,    -   (e) OR^(b),    -   (f) heteroaryl,    -   (g) C₃-C₆ cycloalkyl,    -   (h) C₁-C₆ haloalkyl;

-   R^(b) and R^(c) are independently selected from:    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) aryl,    -   (d) heteroaryl,    -   (e) C₃-C₆ cycloalkyl, and    -   (f) C₁-C₆ haloalkyl; or

-   R^(b) and R^(c) taken together with the N to which they are both    attached form a 3- to 6-membered heterocycle optionally having an    additional heteroatom selected from N, O and S;

-   m is 0, 1, or 2;

-   n is 1, 2 or 3; and

-   p is 1, 2 or 3.

In certain embodiments, provided herein are compounds of Formula I:

or a pharmaceutically acceptable salt, solvate, solvate of the salt,hydrate, a single stereoisomer, a mixture of stereoisomers, a racemicmixture of stereoisomers, or prodrug thereof, wherein:

-   -   Ar is an aryl or a heteroaryl, wherein said aryl and said        heteroaryl are each optionally substituted with 1 to 3        substituents independently selected from:    -   (a) C₁-C₆ alkyl,    -   (b) C₃-C₇ cycloalkyl,    -   (c) heterocycle,    -   (d) aryl,    -   (e) heteroaryl,    -   (f) halogen,    -   (g) CN,    -   (h) OR^(b),    -   (i) N(R^(b))C(═O)R^(c),    -   (j) C(═O)N(R^(b))(R^(c)),    -   (k) S(═O)_(m)R^(b),    -   (l) S(═O)₂N(R^(b))(R^(c)),    -   (m) N(R^(b))S(═O)₂R^(c),    -   (n) SF₅; and    -   (o) C₁-C₆ haloalkyl.

-   W is selected from:    -   (a) C(═O)OR⁵,    -   (b) C(═O)NHOH,    -   (c) S(═O)₂NHR^(b),    -   (d) S(═O)₂NHC(═O)R^(b),    -   (e) NHC(═O)NHSO₂R^(b),    -   (f) 1H-tetrazole,    -   (g) 1,2,4-oxadiazol-5(4H)one,    -   (h) 1,2,4-thiadiazol-5(4H)one,    -   (i) 1,2,4-oxadiazole-5(4H)-thione,    -   (j) 1,2,4-triazole-5(4H)-one,    -   (k) tetrazol-5(4H)-one, and    -   (l) C(═O)NHS(═O)₂R^(b);

-   X¹, X², X³, X⁴, and X⁵ are each independently N or CR^(a), wherein    not more than 2 of X¹, X², X³, X⁴, and X⁵ are N;

-   Y is selected from:    -   (a) a bond,    -   (b) (CH)_(n) wherein 1 to 4 hydrogen atoms may be replaced by        R^(a′),    -   (c) O, and    -   (d) NR^(b);

-   Z is (CH₂)_(n), wherein 1 to 4 hydrogen atoms may be replaced by    R^(a′);

-   R¹ and R² are independently selected from:    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) C₃-C₆ cycloalkyl, and    -   (d) C₁-C₆ haloalkyl;    -   wherein R² is not H; or

-   R¹ and R² taken together represent —(CH₂)_(n)—,    —(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or    —(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—;

-   R³ and R⁴ are independently selected from:    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) C₃-C₆ cycloalkyl,    -   (d) aryl,    -   (e) heteroaryl,    -   (f) halogen,    -   (g) C₁-C₆ haloalkyl; or

-   R³ and R⁴ taken together represent —(CH₂)_(n)—,    —(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or    —(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—; or R¹, R², R³ and R⁴ above are    selected as follows:

-   R¹ is selected from H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, and C₁-C₆    haloalkyl;

-   R³ and R² taken together represent (CH₂)_(n), (CH₂)_(n)O(CH₂)_(p),    (CH₂)_(n)NR^(b)(CH₂)_(p), or (CH₂)_(n)S(═O)_(m)(CH₂)_(p); and

-   R⁴ is selected from H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, aryl,    heteroaryl, halogen and C₁-C₆ haloalkyl;

-   R⁵ is selected from    -   (a) H,    -   (b) C₁-C₆    -   (c) aryl,    -   (d) aralkyl.    -   (e) CH(R⁷)OC(═O)R⁸,    -   (f) CH(R⁷)OC(═O)OR⁸, and    -   (g) a (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl group having the        following formula:

-   -   -   wherein R⁶ is C₁-C₆ alkyl;

-   R⁷ is hydrogen or C₁-C₆ alkyl;

-   R⁸ is C₁-C₆ alkyl or C₃-C₆-cycloalkyl;

-   each R^(a) is independently selected from:    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c)halogen,    -   (d) OR^(b),    -   (e) cyano,    -   (f) C₃-C₆ cycloalkyl, and    -   (g) C₁-C₆ haloalkyl;

-   each R^(a′) is independently selected from:    -   (a) C₁-C₆ alkyl,    -   (b) halogen, and    -   (c) C₁-C₆ haloalkyl;

-   R^(b) and R^(c) are independently selected from:    -   (a) H,    -   (b) C₁-C₆ alkyl,    -   (c) aryl,    -   (d) heteroaryl,    -   (e) C₃-C₆ cycloalkyl, and    -   (f) C₁-C₆ haloalkyl; or

-   R^(b) and R^(c) taken together with the N to which they are both    attached form a 3- to 6-membered heterocycle optionally having an    additional heteroatom selected from N, O and S;

-   m is 0, 1, or 2;

-   n is 1, 2 or 3; and

-   p is 1, 2 or 3.

In certain embodiments, X² is C—R^(a); X¹, X³, X⁴ and X⁵, are eachindependently N or CR^(a); and R^(a) is selected from H, C₁-C₆ alkyl,halogen, aryl, OR^(b), cyano, heteroaryl, C₃-C₆ cycloalkyl, and C₁-C₆haloalkyl.

In yet certain embodiments, X² and X³ are C—R^(a); X¹, X⁴ and X⁵ areeach independently N or CR^(a), wherein not more than 2 of X¹, X⁴ and X⁵are N; and R^(a) is selected from H, C₁-C₆ alkyl, halogen, aryl, OR^(b),cyano, heteroaryl, C₃-C₆ cycloalkyl, and C₁-C₆ haloalkyl.

In yet certain embodiments, X² is CH; and X³ is CH or C-(halogen); X¹,X⁴ and X⁵ are each independently N or CR^(a), wherein not more than 2 ofX¹, X⁴ and X⁵ are N; and R^(a) is selected from H, C₁-C₆ alkyl, halogen,aryl, OR^(b), cyano, heteroaryl, C₃-C₆ cycloalkyl, and C₁-C₆ haloalkyl.In yet certain embodiments, X² is CH; and X³ is CH or C-(halogen); X¹,X⁴ and X⁵ are each independently N or CH, wherein not more than 2 of X¹,X⁴ and X⁵ are N.

In certain embodiments, X¹ is N or C—R^(a); X², X³, X⁴ and X⁵ areC—R^(a); and R^(a) is selected from H, C₁-C₆ alkyl, halogen, aryl,OR^(b), cyano, heteroaryl, C₃-C₆ cycloalkyl, and C₁-C₆ haloalkyl. In yetcertain embodiments, X¹ is N or CH; X² is CH or C-(halogen) and X³, X⁴and X⁵ are CH.

In certain embodiments, each of X¹, X², X³, X⁴ and X⁵ is independentlyC—R^(a), or one of X¹, X², X³, X⁴ and X⁵ is N, and the others are eachindependently C—R^(a).

In certain embodiments, each of X¹, X², X³, X⁴ and X⁵ is independentlyC—R^(a). In yet certain embodiments, each of X¹, X², X³, X⁴ and X⁵ isindependently CH.

In certain embodiments, R^(a) is H or a halogen atom.

In certain embodiments, Z is —CH₂—.

In certain embodiments, Y is a bond or —CH₂—.

In certain embodiments, R¹ and R² taken together represent —CH₂—,—CH₂CH₂— or —CH₂CH₂CH₂.

In certain embodiments, Y is —CH₂—, and R³ and R² taken togetherrepresent —CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂—.

In certain embodiments, Z is —CH₂—; Y is a bond or —CH₂—; R¹ and R²taken together represent —CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂. In yet certainembodiments, Z is —CH₂—; Y is a bond; and R¹ and R² taken togetherrepresent —CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂.

In certain embodiments, Z is —CH₂—; Y is a bond or —CH₂—; and R³ and R²taken together represent —CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂—. In yet certainembodiments, Z is —CH₂—; Y is a bond; and R³ and R² taken togetherrepresent —CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂—. In yet certain embodiments, Zis —CH₂—; Y is a bond; and R³ and R² taken together represent —CH₂—,—CH₂CH₂— or —CH₂CH₂CH₂—; R¹ is H; and R⁴ is selected from H, C₁-C₆alkyl, C₃-C₆ cycloalkyl, aryl, heteroaryl, halogen and C₁-C₆ haloalkyl.

In some embodiments, Ar is aryl or heteroaryl optionally substitutedwith 1 to 3 substituents independently selected from:

-   -   (a) halogen,    -   (b) cyano,    -   (c) C₁-C₆ alkyl,    -   (d) SF₅,    -   (e) C₁-C₆ haloalkyl,    -   (f) OR^(b) wherein R^(b) is C₁-C₆ alkyl, aryl, heteroaryl, C₃-C₆        cycloalkyl or C₁-C₆ haloalkyl,    -   (g) heterocycle,    -   (h) aryl, and    -   (i) heteroaryl.

In certain embodiments, W is selected from:

-   -   (a) C(═O)OR⁵,    -   (b) C(═O)NHOH,    -   (c) S(═O)₂NHR^(b),    -   (d) S(═O)₂NHC(═O)R^(b),    -   (e) NHC(═O)NHSO₂R^(b),    -   (f) 1H-tetrazole,    -   (g) 1,2,4-oxadiazol-5(4H)one,    -   (h) 1,2,4-thiadiazol-5(4H)one,    -   (i) 1,2,4-oxadiazole-5(4H)-thione,    -   (j) 1,2,4-triazole-5(4H)-one,    -   (k) tetrazol-5(4H)-one, and    -   (l) C(═O)NHS(═O)₂R^(b),    -   R⁵ is selected from    -   (h) H,    -   (i) C₁-C₆    -   (j) aryl,    -   (k) aralkyl,    -   (l) CH(R⁷)OC(═O)R⁸,    -   (m) CH(R⁷)OC(═O)OR⁸, and    -   (n) a (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl group having the        following formula:

-   -   -   wherein R⁶ is C₁-C₆ alkyl; and

    -   R^(b) is selected from:

    -   (a) H,

    -   (b) C₁-C₆ alkyl,

    -   (c)aryl,

    -   (d) heteroaryl,

    -   (e)C₃-C₆ cycloalkyl, and

    -   (f) C₁-C₆ haloalkyl.

In certain embodiments, W is CO₂H or 1H-tetrazole.

In some embodiments, the compound is selected from the group consistingof:

-   2-(3-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamido)bicyclo[1.1.1]-pentan-1-yl)acetic    acid;-   2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamido)bicyclo[1.1.1]-pentan-1-yl)acetic    acid;-   2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamido)bicyclo[1.1.1]-pentan-1-yl)acetic    acid;-   2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   2-(3-(1-((4-(trifluoromethyl)phenyl)methyl-d₂)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   6-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   rac-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamido)spiro[3.3]-heptane-2-carboxylic    acid;-   (R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamido)spiro[3.3]-heptane-2-carboxylic    acid;-   (S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamido)spiro[3.3]-heptane-2-carboxylic    acid;-   6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamido)spiro[3.3]-heptane-2-carboxylic    acid;-   (S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamido)spiro[3.3]-heptane-2-carboxylic    acid;rac-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamido)spiro[3.3]-heptane-2-carboxylic    acid;-   (S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamido)spiro[3.3]-heptane-2-carboxylic    acid;-   rac-6-(1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   rac-6-(1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   3-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)propanoic    acid;-   3-(3-methyl-3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)cyclobutyl)propanoic    acid;-   cis-3-(3-methyl-3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)cyclobutyl)-propanoic    acid;-   N-(3-(2-oxo-2-(phenylsulfonamido)ethyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide;-   N-(3-((3-(phenylsulfonyl)ureido)methyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide;-   N-(3-((1H-tetrazol-5-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide;-   2-(4-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[2.1.1]hexan-1-yl)acetic    acid;-   6-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   rac-6-(5-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(5-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(5-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   rac-6-(5-chloro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(5-chloro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(5-chloro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   rac-6-(6-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(6-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(6-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   rac-6-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   rac-6-(1-(4-(difluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (R)-6-(1-(4-(difluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   (S)-6-(1-(4-(difluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   2-(4-(1-(4-(difluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[2.1.1]hexan-1-yl)acetic    acid;-   2-(3-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   2-(4-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[2.1.1]hexan-1-yl)acetic    acid;-   2-(4-(1-((4-(pentafluorothiol)phenyl)methyl)-1H-indole-7-carboxamido)bicyclo[2.1.1]hexan-1-yl)acetic    acid;-   rac-6-(1-((4-(pentafluorothiol)phenyl)methyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   rac-6-(1-(4-(difluoromethyl)benzyl)-4-fluoro-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic    acid;-   2-(3-(1-(4-(difluoromethyl)benzyl)-4-fluoro-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   2-(3-(5-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic    acid;-   2-(3-(1-([1,1′-biphenyl]-4-ylmethyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]    pentan-1-yl)acetic acid;-   2-(3-(1-([1,1′-biphenyl]-4-ylmethyl)-4-fluoro-1H-indole-7-carboxamido)bicyclo[1.1.1]    pentan-1-yl)acetic acid;-   2-(3-(1-([1,1′-biphenyl]-4-ylmethyl)-1H-indazole-7-carboxamido)bicyclo[1.1.1]    pentan-1-yl)acetic acid;-   2-(3-(1-(4-(trifluoromethoxy)benzyl)-1H-indazole-7-carboxamido)bicyclo[1.1.1]    pentan-1-yl)acetic acid;-   2-(3-(4-fluoro-1-(4-iodobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)    acetic acid;-   2-(3-(4-fluoro-1-(4-(pyridine-4-yl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)    acetic acid; and-   2-(3-(4-fluoro-1-(4-morpholinobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)    acetic acid;    or a pharmaceutically acceptable salt, solvate, solvate of the salt    or prodrug thereof.

Some embodiments provided herein describe pharmaceutical compositionscomprising a compound of any of the preceding embodiments, and apharmaceutically acceptable carrier. In some embodiments, thepharmaceutical composition comprises a compound of Formula I, FormulaIa, Formula Ib, Formula Ic, or Formula Id, or a pharmaceuticallyacceptable salt, solvate, solvate of the salt or prodrug thereof, and apharmaceutically acceptable carrier.

Some embodiments provided herein describe methods for the treatment ofcancer comprising administering to a patient in need thereof a compoundor a pharmaceutical composition of any of the preceding embodiments. Insome embodiments, the compound is a compound of Formula I, Formula Ia,Formula Ib, Formula Ic, or Formula Id. In some embodiments, thecomposition comprises a pharmaceutically acceptable carrier and acompound of Formula I, Formula Ia, Formula Ib, Formula Ic, or FormulaId, or a pharmaceutically acceptable salt, solvate, solvate of the saltor prodrug thereof.

In some embodiments, the cancer is selected from the group consisting ofglioblastoma, bone cancer, head and neck cancer, melanoma, basal cellcarcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer,esophageal cancer, gastric cancer, intestinal cancer, colon cancer,bladder cancer, hepatocellular carcinoma, renal cell carcinoma,pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breastcancer, and prostate cancer.

In some embodiments, the treatment further comprises an additional agentselected from an anti-PD-1 antibody and an anti-PD-L1 antibody.

In some instances within any of the preceding embodiments, for compoundsof Formulae I, Ia and Ib, Ar is substituted phenyl. Examples ofsubstituents for phenyl include CN, halomethyl (such as CF₃ and CHF₂)and SF₅. In some embodiments, the substituents for phenyl are CN(cyano), halogen, haloalkyl, phenyl, pyridyl, haloalkoxy, heterocycle,or SF₅.

In some embodiments, each X¹, X², X³, X⁴ and X⁵ is independentlyC—R^(a), or one of X¹, X², X³, X⁴ and X⁵ is N, and the others are eachindependently C—R^(a); and R^(a) is selected from H and halogen (such aschloro and fluoro). Thus, each R^(a) may be the same or different fromthe other R^(a)s. In one instance, X¹, X², X³, X⁴ and X⁵ are each CH. Inanother instance, one of X¹, X², X³, X⁴ and X⁵ is —C(F)— or —C(Cl)— andthe others are each CH.

In some instances within any of the preceding embodiments, for compoundsof Formulae I, Ia and Ib, R¹ and R² together is —CH₂—.

In some instances within any of the preceding embodiments, for compoundsof Formulae I, Ia and Ib, R³ and R² together is —CH₂—.

In some instances within any of the preceding embodiments, for compoundsof Formulae I, Ia and Ib W is —CO₂H, —CONHSO₂-phenyl, —NHCONHSO₂-phenyl,and tetrazolyl. In one instance W is —CO₂H. In another instance W istetrazolyl.

Any of the features of an embodiment is applicable to all embodimentsidentified herein. Moreover, any of the features of an embodiment isindependently combinable, partly or wholly with other embodimentsdescribed herein in any way, e.g., one, two, or three or moreembodiments may be combinable in whole or in part. Further, any of thefeatures of an embodiment may be made optional to other embodiments. Anyembodiment of a method can comprise another embodiment of a compound,and any embodiment of a compound can be configured to perform a methodof another embodiment.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Unless otherwise indicated, conventional methods ofmass spectroscopy, NMR, HPLC, protein chemistry, biochemistry,recombinant DNA techniques and pharmacology are employed. The use of“or” or “and” means “and/or” unless stated otherwise. Furthermore, useof the term “including” as well as other forms, such as “include”,“includes,” and “included,” is not limiting. As used in thisspecification, whether in a transitional phrase or in the body of theclaim, the terms “comprise(s)” and “comprising” are to be interpreted ashaving an open-ended meaning. That is, the terms are to be interpretedsynonymously with the phrases “having at least” or “including at least.”When used in the context of a process, the term “comprising” means thatthe process includes at least the recited steps, but may includeadditional steps. When used in the context of a compound, composition,or device, the term “comprising” means that the compound, composition,or device includes at least the recited features or components, but mayalso include additional features or components.

The term “patient” includes mammals such as mice, rats, cows, sheep,pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans. In someembodiments, the patient is a human.

The term “halo” or “halogen” refers to any radical of fluorine,chlorine, bromine or iodine.

The term “alkyl” refers to a saturated hydrocarbon chain that may be astraight chain or branched chain, containing the indicated number ofcarbon atoms. For example, C₁-C₆ alkyl indicates that the group may havefrom 1 to 6 (inclusive) carbon atoms in it. In some embodiments, analkyl is a C₁-C₆ alkyl which represents a straight-chain or branchedsaturated hydrocarbon radical having 1 to 6 carbon atoms. Examples ofalkyl include without limitation methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, and tert-butyl.

The term “cycloalkyl” refers to a fully saturated monocyclic, bicyclic,tricyclic or other polycyclic hydrocarbon group having the indicatednumber of ring carbon atoms. Multicyclic cycloalkyl may be fused,bridged or spiro ring systems. Cycloalkyl groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and norbornyl. In some embodiments, cycloalkylis a monocyclic C₃-C₈ cycloalkyl.

The term “haloalkyl” refers to an alkyl group in which at least onehydrogen atom is replaced by halo. In some embodiments, more than onehydrogen atom (e.g., 2, 3, 4, 5 or 6) are replaced by halo. In theseembodiments, the hydrogen atoms can each be replaced by the same halogen(e.g., fluoro) or the hydrogen atoms can be replaced by a combination ofdifferent halogens (e.g., fluoro and chloro). “Haloalkyl” also includesalkyl moieties in which all hydrogens have been replaced by halo(sometimes referred to herein as perhaloalkyl, e.g., perfluoroalkyl,such as trifluoromethyl).

As referred to herein, the term “alkoxy” refers to a group of formula—O-(alkyl). Alkoxy can be, for example, methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 2-pentoxy,3-pentoxy, or hexyloxy. Likewise, the term “thioalkoxy” refers to agroup of formula —S-(alkyl). The terms “haloalkoxy” and “thiohaloalkoxy”refer to —O-(haloalkyl) and —S-(haloalkyl), respectively.

The term “aralkyl” refers to an alkyl moiety in which an alkyl hydrogenatom is replaced by an aryl group. One of the carbons of the alkylmoiety serves as the point of attachment of the aralkyl group to anothermoiety. Non-limiting examples of “aralkyl” include benzyl,2-phenylethyl, and 3-phenylpropyl groups.

The term “alkenyl” refers to a straight or branched hydrocarbon chaincontaining the indicated number of carbon atoms and having one or morecarbon-carbon double bonds. Alkenyl groups can include, e.g., vinyl,allyl, 1-butenyl, and 2-hexenyl. In some embodiments, an alkenyl is aC₂-C₆ alkenyl.

The term “alkynyl” refers to a straight or branched hydrocarbon chaincontaining the indicated number of carbon atoms and having one or morecarbon-carbon triple bonds. Alkynyl groups can include, e.g., ethynyl,propargyl, 1-butynyl, and 2-hexynyl. In some embodiments, an alkynyl isa C₂-C₆ alkynyl.

The term “heterocycle”, “heterocyclyl” or “heterocyclic” as used hereinexcept where noted, represents a stable 4-, 5-, 6- or 7-memberedmonocyclic- or a stable 6-, 7-, 8-, 9-, 10-, 11-, or 12-memberedbicyclic heterocyclic ring system which comprises at least onenon-aromatic (i.e. saturated or partially unsaturated) ring whichconsists of carbon atoms and from one to four, preferably up to three,heteroatoms selected from the group consisting of N, O and S, whereinthe nitrogen and sulfur atoms may optionally be oxidized as N-oxide,sulfoxide or sulfone, and wherein the nitrogen atom may optionally bequaternized. A heterocycle can be bonded via a ring carbon atom or, ifavailable, via a ring nitrogen atom. Bicyclic heterocyclic ring systemsmay be fused, bridged, or spiro bicyclic heterocyclic ring system(s). Insome embodiments, heterocyclyl is monocyclic having 4 to 7, preferably 4to 6, ring atoms, of which 1 or 2 are heteroatoms independently selectedfrom the group consisting of N, O and S. In some embodiments, aheterocyclyl group is bicyclic, and in which case, the second ring maybe an aromatic or a non-aromatic ring which consists of carbon atoms andfrom one to four, preferably up to three, heteroatoms independentlyselected from the group consisting of N, O and S, or the second ring maybe a benzene ring, or a “cycloalkyl”, or a “cycloalkenyl”, as definedherein. Examples of such heterocyclic groups include, but are notlimited to azetidine, chroman, dihydrofuran, dihydropyran, dioxane,dioxolane, hexahydroazepine, imidazolidine, imidazoline, indoline,isochroman, isoindoline, isothiazoline, isothiazolidine, isoxazoline,isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, piperazine,piperidine, dihydropyridine, tetrahydropyridine, dihydropyridazine,pyran, pyrazolidine, pyrazoline, pyrrolidine, pyrroline,tetrahydrofuran, tetrahydropyran, thiamorpholine, tetrahydrothiophene,thiazoline, thiazolidine, thiomorpholine, thietane, thiolane, sulfolane,1,3-dioxolane, 1,3-oxazolidine, 1,3-thiazolidine, tetrahydrothiopyran,tetrahydrotriazine, 1,3-dioxane, 1,4-dioxane, hexahydrotriazine,tetrahydro-oxazine, tetrahydropyrimidine, perhydroazepine,perhydro-1,4-diazepine, perhydro-1,4-oxazepine,7-azabicyclo[2.2.1]heptane, 3-azabicyclo[3.2.0]heptane,7-azabicyclo[4.1.0]heptane, 2,5-diazabicyclo[2.2.1]heptane,2-oxa-5-azabicyclo[2.2.1]heptane, tropane, 2-oxa-6-azaspiro[3.3]heptane,dihydrobenzofuran, diydrobenzimidazolyl, dihydrobenzoxazole, anddihydrobenzothiazolyl, and N-oxides or sulfones or sulfoxides thereof.

The term “aryl” as used herein, is intended to mean any stablemonocyclic or bicyclic carbon ring of up to 6 members in each ring(i.e., 6 to 10 total ring atoms) wherein at least one ring is aromatic.For example, a C₆-C₁₀ aryl group such asphenyl, naphthyl,tetrahydronaphthyl, indanyl, or 1H-indenyl. Unless stated otherwisespecifically in the specification, the term “aryl” is meant to includearyl radicals optionally substituted by one or more substituentsindependently selected from CN (cyano), halogen, haloalkyl, —OR^(x),—N(R^(x))₂—, or alkyl; wherein each R^(x) is independently H, alkyl,haloalkyl, cycloalkyl, or heterocyclyl.

The term “heteroaryl”, as used herein except where noted, represents astable 5-, 6- or 7-membered monocyclic- or stable 9- or 10-memberedfused bicyclic ring system which comprises at least one aromatic ring,which consists of carbon atoms and from one to four, preferably up tothree, heteroatoms selected from the group consisting of N, O and Swherein the nitrogen and sulfur heteroatoms may optionally be oxidized,and the nitrogen heteroatom may optionally be quaternized. In the caseof a “heteroaryl” which is a bicyclic group, the second ring need not bearomatic and need not comprise a heteroatom. Accordingly, bicyclic“heteroaryl” includes, for example, a stable 5- or 6-membered monocyclicaromatic ring consisting of carbon atoms and from one to four,preferably up to three, heteroatoms, as defined immediately above, fusedto a benzene ring, or a second monocyclic “heteroaryl”, or a“heterocyclyl”, a “cycloalkyl”, or a “cycloalkenyl”, as defined above.Examples of heteroaryl groups include, but are not limited to,benzimidazole, benzopyrazole, benzisothiazole, benzisoxazole,benzofuran, isobenzofuran, benzothiazole, benzothiophene, benzotriazole,benzoxazole, cinnoline, furan, furazan, imidazole, indazole, indole,indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, phthalazine, pteridine, purine, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline,quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine,triazole, benzimidazole, benzothiadiazole, isoindole, pyrrolopyridines,imidazopyridines such as imidazo[1,2-a]pyridine, pyrazolopyridine,pyrrolopyrimidine and N-oxides thereof. Unless stated otherwisespecifically in the specification, the term “heteroaryl” is meant toinclude heteroaryl radicals optionally substituted by one or moresubstituents independently selected from CN (cyano), halogen, haloalkyl,—OR^(x), —N(R^(x))₂—, or alkyl; wherein each R^(x) is independently H,alkyl, haloalkyl, cycloalkyl, or heterocyclyl.

The term “treating”, “treat”, or “treatment” refers generally tocontrolling, alleviating, ameliorating, slowing the progress of oreliminating a named condition once the condition has been established.In addition to its customary meaning, the term “preventing”, “prevent”,or “prevention” also refers to delaying the onset of, or reducing therisk of developing a named condition or of a process that can lead tothe condition, or the recurrence of symptoms of a condition.

The term “therapeutically effective amount” or “effective amount” is anamount sufficient to effect beneficial or desired clinical results. Aneffective amount can be administered in one or more administrations. Aneffective amount is typically sufficient to palliate, ameliorate,stabilize, reverse, slow or delay the progression of the disease state.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).

Compound Forms and Salts

In some embodiments, the compounds described herein contain one or moreasymmetric centers and thus occur as racemates and racemic mixtures,enantiomerically enriched mixtures, single enantiomers, individualdiastereomers and diastereomeric mixtures. In some embodiments, thecompounds described herein, either by nature of asymmetric centers or byrestricted rotation, be present in the form of isomers (e.g.,enantiomers, diastereomers).

It will also be appreciated that when two or more asymmetric centers arepresent in the compounds of the disclosure, several diastereomers andenantiomers of the exemplified structures will often be possible, andthat pure diastereomers and pure enantiomers represent preferredembodiments. It is intended that pure stereoisomers, pure diastereomers,pure enantiomers, and mixtures thereof, are within the scope of thedisclosure. When compounds contains stereochemistry, the compounds aredesignated as ‘(racemic)’ or “rac” if the stereoisomers have not beenseparated and ‘(R) or (S)’ if the stereoisomers have been resolved. Incertain embodiments, the compounds disclosed herein contain axialchirality, particularly in the case of the spirocyclic[3.3]heptanecontaining compounds. These have also been designed as either ‘(R) or(S)’ when there is a single stereoisomer, rather than the IUPACconvention of ‘(aR) or (aS)’, where the ‘a’ denotes axial chirality.

All isomers, whether separated, pure, partially pure, or in racemicmixture, of the compounds of this disclosure are encompassed within thescope of this disclosure. The purification of said isomers and theseparation of said isomeric mixtures may be accomplished by standardtechniques known in the art. For example, diastereomeric mixtures can beseparated into the individual isomers by chromatographic processes orcrystallization, and racemates can be separated into the respectiveenantiomers either by chromatographic processes on chiral phases or byresolution.

The compounds of the present disclosure include all cis, trans, syn,anti, entgegen (E), and zusammen (Z) isomers as well as mixturesthereof. In some embodiments, the compounds described herein exist inmultiple tautomeric forms. In such instances, the present disclosureexpressly includes all tautomeric forms of the compounds describedherein, even though only a single tautomeric form may be represented. Inaddition, where a term used in the present disclosure encompasses agroup that may tautomerize, all tautomeric forms are expressly includedthereunder. For example, hydroxy substituted heteroaryl includes2-hydroxypyridine as well as 2-pyridone, 1-hydroxyisoquinoline as wellas 1-oxo-1,2-dihyroisoquinoline, and the like. All such isomeric formsof such compounds are expressly included in the present disclosure.

The compounds of the present disclosure include the compoundsthemselves, as well as their salts, solvate, solvate of the salt andtheir prodrugs, if applicable. Salts for the purposes of the presentdisclosure are preferably pharmaceutically acceptable salts of thecompounds according to the present disclosure. Salts which are notthemselves suitable for pharmaceutical uses but can be used, forexample, for isolation or purification of the compounds according to thedisclosure are also included. A salt, for example, can be formed betweenan anion and a positively charged substituent (e.g., amino) on acompound described herein. Suitable anions include chloride, bromide,iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate,trifluoroacetate, and acetate. Likewise, a salt can also be formedbetween a cation and a negatively charged substituent (e.g.,carboxylate) on a compound described herein. Suitable cations includesodium ion, potassium ion, magnesium ion, calcium ion, and an ammoniumcation such as tetramethylammonium ion.

As used herein, “pharmaceutically acceptable salts” refer to derivativeswherein the parent compound is modified by making acid or base saltsthereof. Examples of pharmaceutically acceptable salts include, but arenot limited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like. When the compound of the present disclosure isbasic, pharmaceutically acceptable salts include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Forexample, such conventional non-toxic salts include those derived frominorganic acids such as hydrochloric, hydrobromic, sulfonic, sulfuric,sulfamic, phosphoric, nitric and the like; and the salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxybenzoic, fumaric, benzenesulfonic, toluenesulfonic,naphthalenedisulfonic, methanesulfonic, ethanesulfonic,ethanedisulfonic, camphorsulfonic, gluconic, mandelic, mucic,pantothenic, oxalic, isethionic, and the like.

When the compound of the present disclosure is acidic, salts may beprepared from pharmaceutically acceptable non-toxic bases, includinginorganic and organic bases. In some embodiments, the pharmaceuticallyacceptable salt is lithium salt, sodium salt, potassium salt, magnesiumsalt, calcium salt, dicyclohexylamine salt, N-methyl-D-glucamine salt,tris(hydroxymethyl)methylamine salt, arginine salt, lysine salt, and thelike.

Lists of suitable salts may be found in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418;S. M. Berge et al., “Pharmaceutical Salts”, J. Pharm. Sci. 1977, 66,1-19; and “Pharmaceutical Salts: Properties, Selection, and Use. AHandbook”; Wermuth, C. G. and Stahl, P. H. (eds.) Verlag HelveticaChimica Acta, Zurich, 2002 [ISBN 3-906390-26-8]; each of which isincorporated herein by reference in its entirety.

Solvates in the context of the present disclosure are designated asthose forms of the compounds according to the present disclosure whichform a complex in the solid or liquid state by stoichiometriccoordination with solvent molecules. Hydrates are a specific form ofsolvates, in which the coordination takes place with water. Hydrates arepreferred solvates in the context of the present disclosure. Theformation of solvates is described in greater detail in “Solvents andSolvent Effects in Organic Chemistry”; Reichardt, C. and Welton T.; JohnWiley & Sons, 2011 [ISBN: 978-3-527-32473-6], the contents of which isincorporated herein by reference in its entirety. A person of ordinaryskill in the art would recognize the solvates of the present disclosure.

The present disclosure also encompasses all suitable isotopic variantsof the compounds according to the present disclosure, whetherradioactive or not. An isotopic variant of a compound according to thepresent disclosure is understood to mean a compound in which at leastone atom within the compound according to the present disclosure hasbeen exchanged for another atom of the same atomic number, but with adifferent atomic mass than the atomic mass which usually orpredominantly occurs in nature. Examples of isotopes which can beincorporated into a compound according to the present disclosure arethose of hydrogen, carbon, nitrogen, oxygen, fluorine, chlorine, bromineand iodine, such as ²H (deuterium), ³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷O,¹⁸O, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁵I, ¹²⁹I and ¹³¹I. Particularisotopic variants of a compound according to the present disclosure,especially those in which one or more radioactive isotopes have beenincorporated, may be beneficial, for example, for the examination of themechanism of action or of the active compound distribution in the body.Due to comparatively easy preparability and detectability, especiallycompounds labelled with ³H, ¹⁴C and/or ¹⁸F isotopes are suitable forthis purpose. In addition, the incorporation of isotopes, for example ofdeuterium, can lead to particular therapeutic benefits as a consequenceof greater metabolic stability of the compound, for example an extensionof the half-life in the body or a reduction in the active dose required.Such modifications of the compounds according to the present disclosuremay therefore in some cases also constitute a preferred embodiment ofthe present disclosure. In some embodiments, hydrogen atoms of thecompounds described herein may be replaced with deuterium atoms.Isotopic variants of the compounds according to the present disclosurecan be prepared by processes known to those skilled in the art, forexample by the methods described below and the methods described in theworking examples, by using corresponding isotopic modifications of theparticular reagents and/or starting compounds therein.

The present disclosure includes within its scope prodrugs of thecompounds of Formula I, and Formulae Ia, Ib, Ic, and Id. Prodrugs aregenerally drug precursors that, following administration to a subjectare converted to an active, or a more active species via some process,such as conversion by chemical hydrolysis or a metabolic pathway. Thus,in the methods of treatment of the present disclosure, the terms“administration of” or “administering a” compound shall encompass thetreatment of the various conditions described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985(Amsterdam, NL), the contents of which is incorporated herein byreference in its entirety. Examples of prodrugs include C₁-C₆ alkylesters of carboxylic acid group, which, upon administration to asubject, are capable of providing active compounds.

Pharmaceutical Compositions

The term “pharmaceutical composition” as used herein is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present disclosure encompass anycomposition made by admixing a compound of the present disclosure, or apharmaceutically acceptable salt, or solvate or solvate of the saltthereof, and a pharmaceutically acceptable carrier.

The term “pharmaceutically acceptable carrier” refers to a carrier or anadjuvant that may be administered to a patient, together with a compoundof the present disclosure, or a pharmaceutically acceptable salt,solvate, salt of the solvate or prodrug thereof, and which does notdestroy the pharmacological activity thereof and is nontoxic whenadministered in doses sufficient to deliver a therapeutic amount of thecompound.

In some embodiments, the compounds of the present application areadministered at about 1 mg to 1,000 mg, about 2 mg to 900 mg, about 3 mgto 800 mg, about 4 mg to 700 mg, about 5 mg to 600 mg, about 10 mg to500 mg, about 50 mg to 400 mg, about 100 mg to 300 mg, about 150 mg to250 mg, or any value in between. In some embodiments, the total dailydosage may be divided and administered in portions during the day, forexample, once per day, twice per day, three times per day or four timesper day. In some embodiments, the total dosage may be administered onceper week, twice per week, three times per week, four times per week,five times per week or six times per week.

In some embodiments, the pharmaceutical compositions of the presentdisclosure for injection comprise pharmaceutically acceptable sterileaqueous or non-aqueous solutions, dispersions, suspensions or emulsionsas well as sterile powders for reconstitution into sterile injectablesolutions or dispersions just prior to use. Examples of suitable aqueousand non-aqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

In some embodiments, the pharmaceutical compositions may also containadjuvants such as preservative, wetting agents, emulsifying agents, anddispersing agents. Prevention of the action of micro-organisms may beensured by the inclusion of various antibacterial and antifungal agents,for example, paraben, chlorobutanol, phenol sorbic acid, and the like.It may also be desirable to include isotonic agents such as sugars,sodium chloride, and the like. Prolonged absorption of the injectablepharmaceutical form may be brought about by the inclusion of agents thatdelay absorption such as aluminium monostearate and gelatin. If desired,and for more effective distribution, the compounds can be incorporatedinto slow release or targeted delivery systems such as polymer matrices,liposomes, and microspheres.

In some embodiments, the pharmaceutical compositions that are injectableformulations can be sterilised, for example, by filtration through abacterial-retaining filter, or by incorporating sterilising agents inthe form of sterile solid pharmaceutical compositions that can bedissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

In some embodiments, solid dosage forms of the instant pharmaceuticalcompositions for oral administration. In some embodiments, the oraldosage forms include capsules, tablets, pills, powders, and granules. Insuch solid dosage forms, the active compound is mixed with at least oneinert, pharmaceutically acceptable excipient or carrier such as sodiumcitrate or dicalcium phosphate and/or a) fillers or extenders such asstarches, lactose, sucrose, glucose, mannitol, and silicic acid, b)binders such as, for example, carboxymethylcellulose, alginates,gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants suchas glycerol, d) disintegrating agents such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate, e) solution retarding agents such as paraffin, f)absorption accelerators such as quaternary ammonium compounds, g)wetting agents such as, for example, cetyl alcohol and glycerolmonostearate, h) absorbents such as kaolin and bentonite clay, and i)lubricants such as talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Inthe case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents.

Solid pharmaceutical compositions of a similar type may also be employedas fillers in soft and hard-filled gelatin capsules using suchexcipients as lactose or milk sugar as well as high molecular weightpolyethylene glycols and the like.

The solid dosage forms of the instant pharmaceutical compositions oftablets, dragées, capsules, pills, and granules can be prepared withcoatings and shells such as enteric coatings and other coatings wellknown in the pharmaceutical formulating art. They may optionally containopacifying agents and can also be of a formulation that they release theactive ingredient(s) only, or preferentially, in a certain part of theintestinal tract, optionally, in a delayed manner. Examples of embeddingpharmaceutical compositions which can be used include polymericsubstances and waxes.

The active compounds can also be in microencapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Some embodiments provide liquid dosage forms of the instantpharmaceutical compositions for oral administration. In someembodiments, the liquid dosages include pharmaceutically acceptableemulsions, solutions, suspensions, syrups and elixirs. In addition tothe active compounds, the liquid dosage forms may contain inert diluentscommonly used in the art such as, for example, water or other solvents,solubilizing agents and emulsifiers such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide,oils (in particular, cottonseed, groundnut, corn, germ, olive, castor,and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral pharmaceutical compositions can alsoinclude adjuvants such as wetting agents, emulsifying and suspendingagents, sweetening, flavouring, and perfuming agents.

Suspensions of the instant compounds, in addition to the activecompounds, may contain suspending agents as, for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminium metahydroxide, bentonite,agar-agar, and tragacanth, and mixtures thereof.

Pharmaceutical compositions for rectal or vaginal administration arepreferably suppositories which can be prepared by mixing the compoundswith suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol or a suppository wax which are solid at roomtemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Dosage forms for topical administration of a compound or pharmaceuticalcomposition of the present disclosure include powders, patches, sprays,ointments and inhalants. The active compound is mixed under sterileconditions with a pharmaceutically acceptable carrier and any neededpreservatives, buffers, or propellants which may be required.

Uses

Some embodiments provide methods of treating cancer, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of Formula I, or a pharmaceutically acceptablesalt, solvate, solvate of a salt, or a prodrug thereof. In someembodiments the cancers include, but are not limited to: glioblastoma,bone cancer, head and neck cancer, melanoma, basal cell carcinoma,squamous cell carcinoma, adenocarcinoma, oral cancer, esophageal cancer,gastric cancer, intestinal cancer, colon cancer, bladder cancer,hepatocellular carcinoma, renal cell carcinoma, pancreatic cancer,ovarian cancer, cervical cancer, lung cancer, breast cancer, andprostate cancer. In some embodiments, the cancer is glioblastoma. Insome embodiments, the cancer is melanoma, basal cell carcinoma, orsquamous cell carcinoma. In some embodiments, the cancer is head andneck cancer, oral cancer, or esophageal cancer. In some embodiments, thecancer is bone cancer. In some embodiments, the cancer isadenocarcinoma. In some embodiments, the cancer is gastric cancer,intestinal cancer, colon cancer, or bladder cancer. In some embodiments,the cancer is hepatocellular carcinoma or renal cell carcinoma. In someembodiments, the cancer is pancreatic cancer. In some embodiments, thecancer is lung cancer. In some embodiments, the cancer is non-small celllung cancer. In some embodiments, the cancer is prostate cancer. In someembodiments, the cancer is ovarian cancer or cervical cancer. In someembodiments, the cancer is breast cancer. In some embodiments, thecompound of Formula I, or a pharmaceutically acceptable salt thereof, isa compound of Formulae Ia, Ib, Ic, Id, or a pharmaceutically acceptablesalt of any of the foregoing.

Some embodiments provide methods preventing the onset of and/orrecurrence of cancer, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula I,or a pharmaceutically acceptable salt, solvate, solvate of a salt, or aprodrug thereof.

Some embodiments provide methods of treating cancer, comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a composition comprising a compound of Formula I, or apharmaceutically acceptable salt, solvate, solvate of a salt, or aprodrug thereof. In some embodiments the cancers include, but are notlimited to: glioblastoma, bone cancer, head and neck cancer, melanoma,basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, oralcancer, esophageal cancer, gastric cancer, intestinal cancer, coloncancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma,pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breastcancer, and prostate cancer. In some embodiments, the cancer isglioblastoma. In some embodiments, the cancer is melanoma, basal cellcarcinoma, or squamous cell carcinoma. In some embodiments, the canceris head and neck cancer, oral cancer, or esophageal cancer. In someembodiments, the cancer is bone cancer. In some embodiments, the canceris adenocarcinoma. In some embodiments, the cancer is gastric cancer,intestinal cancer, colon cancer, or bladder cancer. In some embodiments,the cancer is hepatocellular carcinoma or renal cell carcinoma. In someembodiments, the cancer is pancreatic cancer. In some embodiments, thecancer is lung cancer. In some embodiments, the cancer is non-small celllung cancer. In some embodiments, the cancer is prostate cancer. In someembodiments, the cancer is ovarian cancer or cervical cancer. In someembodiments, the cancer is breast cancer. In some embodiments, thecompound of Formula I, or a pharmaceutically acceptable salt thereof, isa compound of Formulae Ia, Ib, Ic, Id, or a pharmaceutically acceptablesalt of any of the foregoing.

Some embodiments provide methods preventing the onset of and/orrecurrence of cancer, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula I,or a pharmaceutically acceptable salt, solvate, solvate of a salt, or aprodrug thereof.

Some embodiments provide a compound of Formula I for use in treatingcancer. In some embodiments the cancers include, but are not limited to:glioblastoma, bone cancer, head and neck cancer, melanoma, basal cellcarcinoma, squamous cell carcinoma, adenocarcinoma, oral cancer,esophageal cancer, gastric cancer, intestinal cancer, colon cancer,bladder cancer, hepatocellular carcinoma, renal cell carcinoma,pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breastcancer, and prostate cancer. In some embodiments, the cancer isglioblastoma. In some embodiments, the cancer is melanoma, basal cellcarcinoma, or squamous cell carcinoma. In some embodiments, the canceris head and neck cancer, oral cancer, or esophageal cancer. In someembodiments, the cancer is bone cancer. In some embodiments, the canceris adenocarcinoma. In some embodiments, the cancer is gastric cancer,intestinal cancer, colon cancer, or bladder cancer. In some embodiments,the cancer is hepatocellular carcinoma or renal cell carcinoma. In someembodiments, the cancer is pancreatic cancer. In some embodiments, thecancer is lung cancer. In some embodiments, the cancer is non-small celllung cancer. In some embodiments, the cancer is prostate cancer. In someembodiments, the cancer is ovarian cancer or cervical cancer. In someembodiments, the cancer is breast cancer.

Some embodiments provide a compound of Formula I for use in preventingthe onset of and/or recurrence of cancer.

Some embodiments provide a compound of Formula I for the preparation ofa medicament for treating cancer. In some embodiments the cancersinclude, but are not limited to: glioblastoma, bone cancer, head andneck cancer, melanoma, basal cell carcinoma, squamous cell carcinoma,adenocarcinoma, oral cancer, esophageal cancer, gastric cancer,intestinal cancer, colon cancer, bladder cancer, hepatocellularcarcinoma, renal cell carcinoma, pancreatic cancer, ovarian cancer,cervical cancer, lung cancer, breast cancer, and prostate cancer. Insome embodiments, the cancer is glioblastoma. In some embodiments, thecancer is melanoma, basal cell carcinoma, or squamous cell carcinoma. Insome embodiments, the cancer is head and neck cancer, oral cancer, oresophageal cancer. In some embodiments, the cancer is bone cancer. Insome embodiments, the cancer is adenocarcinoma. In some embodiments, thecancer is gastric cancer, intestinal cancer, colon cancer, or bladdercancer. In some embodiments, the cancer is hepatocellular carcinoma orrenal cell carcinoma. In some embodiments, the cancer is pancreaticcancer. In some embodiments, the cancer is lung cancer. In someembodiments, the cancer is non-small cell lung cancer. In someembodiments, the cancer is prostate cancer. In some embodiments, thecancer is ovarian cancer or cervical cancer. In some embodiments, thecancer is breast cancer.

Some embodiments provide a compound of Formula I for the preparation ofa medicament for use in preventing the onset of and/or recurrence ofcancer.

Administration

The compounds and compositions described herein can, for example, beadministered orally, parenterally (e.g., subcutaneously,intracutaneously, intravenously, intramuscularly, intraarticularly,intraarterially, intrasynovially, intrasternally, intrathecally,intralesionally and by intracranial injection or infusion techniques),by inhalation spray, topically, rectally, nasally, buccally, vaginally,via an implanted reservoir, by injection, subdermally,intraperitoneally, transmucosally, or in an ophthalmic preparation, witha dosage ranging from about 0.01 mg/kg to about 1000 mg/kg, or any valuein between (e.g., from about 0.01 to about 100 mg/kg, from about 0.1 toabout 100 mg/kg, from about 1 to about 100 mg/kg, from about 1 to about10 mg/kg, or any value in between) every 4 to 120 hours, or any value inbetween. The interrelationship of dosages for animals and humans (basedon milligrams per meter squared of body surface) is described byFreireich et al., Cancer Chemother. Rep. 50, 219-244 (1966) and isunderstood by those skilled in the art. Body surface area may beapproximately determined from height and weight of the patient by thoseskilled in the art. See, e.g., Scientific Tables, Geigy Pharmaceuticals,Ardsley, N.Y., 537 (1970). In certain embodiments, the compositions areadministered by oral administration or by injection. The methods hereincontemplate administration of an effective amount of compound orcompound composition to achieve the desired or stated effect. Typically,the pharmaceutical compositions of the present disclosure will beadministered from about 1 to about 6 times per day or alternatively, asa continuous infusion. Such administration can be used as a chronic oracute therapy.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, and the judgment of the treating physician.

In some embodiments, dosage forms include from about 0.001 milligrams toabout 2,000 milligrams, or any value in between (including, from about0.001 milligrams to about 1,000 milligrams, from about 0.001 milligramsto about 500 milligrams, from about 0.01 milligrams to about 250milligrams, from about 0.01 milligrams to about 100 milligrams, fromabout 0.05 milligrams to about 50 milligrams, and from about 0.1milligrams to about 25 milligrams, or any value in between) of acompound of Formula I (and/or a compound of any of the other formulaedescribed herein) or a salt (e.g., a pharmaceutically acceptable salt)thereof as defined anywhere herein. The dosage forms can further includea pharmaceutically acceptable carrier and/or an additional therapeuticagent.

Appropriate dosage levels may be determined by any suitable method knownto one skilled in the art of treating cancer. Preferably, the activesubstance is administered at a frequency of 1 to 4 times per day fortopical administration, or less often if a drug delivery system is used.

Nevertheless, actual dosage levels and time course of administration ofthe active ingredients in the pharmaceutical compositions of the presentdisclosure may be varied so as to obtain an amount of the activeingredient which is effective to achieve the desired therapeuticresponse for a particular patient, composition and mode ofadministration, without being toxic to the patient. It may therefore benecessary where appropriate to deviate from the stated amounts, inparticular as a function of age, gender, body weight, diet and generalhealth status of the patient, route of administration, individualresponse to the active ingredient, nature of the preparation, and timeor interval over which administration takes place. Thus, it may besatisfactory in some cases to manage with less than the aforementionedminimum amount, whereas in other cases the stated upper limit must beexceeded. It may in the event of administration of larger amounts beadvisable to divide these into multiple individual doses spread over theday.

In some embodiments, the compounds of the present disclosure may beco-administered with one or more additional agents used in the treatmentof cancer. In some embodiments, the additional agents include, but arenot limited to: alkylating agents such as cyclophosphamide,chlorambucil, meclorethamine, ifosfamide, or melphalan; antimetabolitessuch as methotrexate, cytarabine, gemcitabine, fludarabine,6-mercaptopurine, azathioprene, or 5-fluorouracil; antimitotic agentssuch as vincristine, vinblastine, vindesine, vinorelbine, paclitaxel, ordocetaxel; platinum derivatives such as cisplatin, carboplatin oroxaliplatin; hormone therapeutics such as tamoxifen; aromataseinhibitors such as bicalutamide, anastrozole, exemestane or letrozole;signaling inhibitors such as imatinib (tyrosine kinase inhibitor;Gleevac), gefitinib (EGFR inhibitor; Iressa) or erlotinib (receptor TKI,which acts on EGFR; Tarceva); monoclonal antibodies such as trastuzumab,pertuzumab, inotuzumab, or ozogamicins thereof, as well as otherantibody-drug conjugates such as ado-trastuzumab emtansine;antiangiogenic agents such as bevacizumab, sorafenib (tyrosine proteinkinase), pazopanib or sunitinib (receptor tyrosine kinase inhibitor);tivozanib, axitinib, and cediranib; -tinib (tyrosine kinase inhibitors)such as lapatinib; biologic response modifiers such as interferon-alpha;topoisomerase inhibitors such as camptothecins (including irinotecan andtopotecan), amsacrine, etoposide, etoposide phosphate, or teniposide;anthracyclines such as doxorubicin, daunorubicin, epirubicin,idarubicin, sabarubicin, aclarubicin, carubicin and valrubicin; othercytotoxic agents such as actinomycin, bleomycin, plicamycin ormitomycin; mTOR inhibitors such as rapamycin, temsirolimus andeverolimus; and antibody therapy such as CTLA4 antibody therapy, PDL1antibody therapy, and PD1 antibody therapy.

The terms “CTLA4 antibody” and “anti-CTLA4” refer to an antibody orantibodies directed towards cytotoxic t-lymphocyte antigen 4 (CTLA4).Exemplary antibodies include, but are not limited to, antibodies thatare CTLA4 antagonists or the CTLA4 antibodies as set forth in U.S. Pat.Nos. 8,685,394 and 8,709,417. Some embodiments of the antibody includeipilimumab (YERVOY®, Bristol-Myers Squibb) and CP-675,206 (tremelimumab,Pfizer). In a particular embodiment, the antibody is ipilimumab.

“PDL1 antibody” or “anti-PDL1” refers to an antibody directed towardsprogrammed death ligand 1 (PDL1). Exemplary antibodies include, but arenot limited to, the antibodies set forth in U.S. Pat. Nos. 8,217,149,8,383,796, 8,552,154 and 8,617,546. Some embodiments of the antibodyinclude avelumab (Merck KGA/Pfizer), durvalumab (AstraZeneca) andatezolizumab (TECENTRIQ®, Roche). In a particular embodiment, theantibody is atezolizumab.

The terms “PD1 antibody” and “anti-PD1” refers to an antibody directedtowards programmed death protein 1 (PD1). Exemplary antibodies include,but are not limited to, the antibodies set forth in U.S. Pat. Nos.7,029,674, 7,488,802, 7,521,051, 8,008,449, 8,354,509, 8,617,546 and8,709,417. Particular embodiments of the antibody include BGB-A317,nivolumab (OPDIVO®, Bristol-Myers Squibb), labrolizumab (Merck), andpembrolizumab (KEYTRUDA®, Merck).

In some embodiments, the antibody, e.g., anti-CTLA4, anti-PDL1 oranti-PD1, will be mixed, prior to administration, with a non-toxic,pharmaceutically acceptable carrier substance (e.g., normal saline orphosphate-buffered saline), and may be administered using any medicallyappropriate procedure, for example, including but not limited to,intravenous or intra-arterial administration, and injection into thecerebrospinal fluid. In certain cases, intraperitoneal intradermal,intracavity, intrathecal or direct administration to a tumor or to anartery supplying the tumor may be advantageous.

The terms “antibody” and “antibodies” as used herein is inclusive of alltypes of immunoglobulins, including IgG, IgM, IgA, IgD, and IgE, orfragments thereof, that may be appropriate for the medical usesdisclosed herein. The antibodies may be monoclonal or polyclonal and maybe of any species of origin, including, for example, mouse, rat, rabbit,horse, or human. Antibody fragments that retain specific binding to theprotein or epitope, for example, CTLA4, PDL1 or PD1, bound by theantibody used in the present disclosure are included within the scope ofthe term “antibody.” Such fragments can be produced by known techniques.The antibodies may be chimeric or humanized, particularly when they areused for therapeutic purposes. The antibody may be obtained or preparedusing methods known in the art.

In some embodiments, other immunotherapy targets such as IDO inhibitors,e.g., epacadostat may also be used in combination with compounds of thepresent disclosure.

In some embodiments, the additional agents may be administeredseparately from the compounds of the present disclosure as part of amultiple dose regimen (e.g., sequentially, or on different overlappingschedules with the administration of one or more compounds of FormulaI). In other embodiments, these agents may be part of a single dosageform, mixed together with the compounds of the present disclosure in asingle composition. In some embodiments, these agents can be given as aseparate dose that is administered at about the same time as one or morecompounds of Formula I are administered (e.g., simultaneously with theadministration of one or more compounds of Formula (I) (and/or acompound of any of the other formulae, including any subgenera orspecific compounds thereof)). In some embodiments, at least one of thetherapeutic agents in the combination therapy is administered using thesame dosage regimen (dose, frequency and duration of treatment) that istypically employed when the agent is used as monotherapy for treatingthe same cancer. In some embodiments, the patient receives a lower totalamount of at least one of the therapeutic agents in the combinationtherapy than when the agent is used as monotherapy, e.g., smaller doses,less frequent doses, and/or shorter treatment duration.

When the compositions of the present disclosure include a combination ofa compound of the formulae described herein and one or more additionalagents, both the compound and the additional agent can be present atdosage levels of between about 1 to 100%, and more preferably betweenabout 5 to 95% of the dosage normally administered in a monotherapyregimen.

Biological Function

The utility of the present disclosure can be demonstrated by one or moreof the following methods or other methods known in the art:

In Vitro Assay

The compounds in the present disclosure were tested in a functionalcalcium flux assay using stably transfected HEK293 cells. Cellstransfected with EP1, EP2, EP3 and EP4 were purchased from EurofinsDiscovery Services (St. Charles, Mo.). Each receptor subtype has anadditional promiscuous G protein added in order to couple to the calciumsignaling pathway. The parental cell line used also expresses a novelvariant of clytin, a calcium-activated photo-protein, to enablesensitive luminescent detection.

Cells were plated at 50,000 cells per well in black, clear bottom96-well plates. The plated cells were allowed to sit at room temperaturefor 30 min prior to transferring to a humidified, 37° C., 5% CO₂incubator for 18-24 h. Assay buffer (HBSS with 20 mM HEPES) and loadingbuffer (assay buffer plus 10 μM Coelenterazine) were prepared on the dayof the assay. Assays were performed by aspirating media from the assayplate and washing once with assay buffer, then replacing with loadingbuffer and allowing the cells to incubate for 1.5 h at room temperature.Compounds were prepared in assay buffer at a 3× final concentration innon binding plates. Compounds were added to the cell plates andincubated for 30 min at room temperature. The prostanoid receptor ligandPGE2 was prepared at a 4× dilution ratio for a final concentration of 10nM. Plates were run on a Flexstation™ using a 100 ms integrationluminescence protocol for a total of 60 sec with ligand addition at 15sec. Data were obtained from relative light units as measured by areaunder the curve.

TABLE 1 EP₄ Ca²⁺-flux assay IC₅₀ Example MS (ESI⁺) MS (ESI⁻) (nM)  1 400398 13  2 443 441 1.5  3 444 442 160  5 444 442 930  6 444 442 19  7 445443 2.0  8, first eluting 457 455 520  8, second eluting 457 455 0.19  9458 456 6.0 10, first eluting 458 456 20 10, second eluting 458 456 0.1311 458 456 24 12 458 456 2.7 13 458 456 32 14 459 457 9.0 15 459 457 40016 582 580 140 17 597 595 130 18 467 465 1.5 19 457 455 9.1 20, firsteluting 475 473 24 20, second eluting 475 473 0.31 21 475 473 0.31 23475 473 0.3 24 414 412 10 25 439 437 0.4 26 439 437 3.8 27 461 459 0.528 475 473 0.6 29 515 513 1.2 30 515 513 0.2 31 457 455 0.03 32 443 4410.1 33 461 459 0.1 34 451 449 0.22 35 469 467 0.28 36 452 450 0.32 37460 458 75 38 519 517 — 39 470 468 — 40 478 476 —

In Vivo Tumor Model

Female Balb/C mice were implanted with 1×10⁶ CT26 colon cancer cells(ATCC® CRL-2638) in a 2×10⁶ cells/mL ++PBS solution. Cells were injectedsubcutaneously into the left hind flank. Tumors were measured withcalipers and tumor volumes calculated using the formula: tumorvolume=(length×width)/2. When tumor volumes were ˜150 mm³, mice wererandomized into groups (10 animals per group) and treated with eithervehicle (0.5% methocel PO, bid for 11 days) or test compound (30 mg/kgPO, bid for 11 days). Tumor volumes were determined 3 times a week untilstudy termination. Results for compound A are provided in FIGS. 1A and1B.

Preparation of Compounds

The starting materials used for the synthesis are either synthesized orobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, Enamine, PharmaBlock,VWR Scientific, and the like. The reversed phase and normal phasechromatography columns were purchased from Teledyne ISCO, Inc. (NE).Nuclear Magnetic Resonance (NMR) analysis was conducted using a BrukerFourier 300 MHz spectrometer with an appropriate deuterated solvent.LCMS spectra were obtained on a Shimazu LCMS-2020 Series massspectrometer using Electrospray Ionization (ESI) and a Luna C18 5 μM,2.0×50 mm column, eluting with 95:5 to 0:100 H2O:MeCN+0.1% formic acidat a flow rate of 0.7 mL/min over 3.5 minutes. General methods for thepreparation of compounds can be modified by the use of appropriatereagents and conditions for the introduction of the various moietiesfound in the structures as provided herein.

Abbreviations

Aq. Aqueous BrettPhos2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl CDI Carbonyldiimidazole DABCO1,4-diazabicyclo[2.2.2]octane DCC N,N′-dicyclohexylcarbodiimide DMAP4-dimethylaminopyridine DMF Dimethylformamide e.e. Enantiomeric excessEDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Eq. Equivalent(s)EtOAc Ethyl acetate h Hour(s) HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium3-oxide hexafluorophosphate Hex Hexanes LC-MS Liquid chromatography/massspectrometry (Shimazu, Model#: LCMS-2020) M Molar MeCN AcetonitrileMe-THF 2-methyltetrahydrofuran min Minute(s) N Normal NMPN-methyl-2-pyrrolidone O/N Overnight ++PBS Phosphate buffered salinewith added calcium(II) and magnesium(II) PMHS polymethylhydrosiloxaneRBF Round bottom flask RT Room temperature RuPhos2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl SFC Supercriticalfluid chromatography T3P Propylphosphonic anhydride TFA Trifluoraceticacid THF Tetrahydrofuran TMSI Trimethylsilyl iodide v volume XPhos2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propylbiphenyl

General Synthetic Scheme

Compounds of formula I of the present disclosure may be prepared, forexample, from an amine (1), or its corresponding ammonium salt, and acarboxylic acid (2) in the presence of an appropriate coupling reagentsuch as HATU, CDI, or the like, and an appropriate base such astriethylamine, ethyl-diisopropyl-amine, or the like. Alternatively, theacid may be pre-activated via its conversion into the corresponding acidchloride using an agent such as thionyl chloride, oxalyl chloride, orthe like. The resulting amide 3 is converted into the targeted compoundI using synthetic methodologies appropriate for the identity of thefunctional group “G” in 3 and the desired identity of the functionalgroup “W” in I. Examples of such conversions include, but are notlimited to:

(a) ester hydrolysis (i.e. “G”=CO₂R, where R can be methyl, ethyl,benzyl, tert-butyl, or the like; and “W”=CO₂H) using well-knownconditions such as acid-mediated hydrolysis (i.e. HCl, TFA, H₂SO₄, orthe like), base-mediated hydrolysis (i.e. NaOH, LiOH, Bu₄NOH, or thelike), nucleophile-mediated hydrolysis (i.e. LiI, TMSI, Me₃SnOH or thelike), enzyme-mediated hydrolysis (pig liver esterase, Candidaantarctica lipase, Candida rugosa lipase, or the like), metal-mediatedhydrogenolysis (Pd/C and H₂, Pd(PPh₃)₄ and PMHS, or the like), andothers.

Alternatively, the aforementioned ester group can first be derivatized(i.e. mono- or bis-alkylation or arylation at the α-carbon via thecorresponding enolate, if accessible, or the like) prior to hydrolysis.

(b) reaction of nitrile (i.e. “G”=CN)—

-   -   (i) to form a tetrazole (i.e. “W”=

by heating 3 with an appropriate azide source (i.e. NaN₃, Bu₃SnN₃,Bu₄NN₃, or the like), most often in the presence of an appropriatepromoter (i.e. ZnBr₂, Bu₂Sn═O, NH₄Cl, or the like);

-   -   (ii) to form an oxadiazalone (i.e. “W”=

by heating 3 with hydroxylamine and then treating the resultingN-hydroxyamidine with CDI, or the like; and

-   -   (iii) to form a carboxylic acid (i.e. “W”=CO₂H) by heating 3        with aqueous KOH and ethylene glycol, or the like.

(c) elaboration of carboxylic acid (i.e. “G”=CO₂H)—

-   -   (i) using Arndt-Eistert homologation or the like, in cases where        Y is a bond, to provide the corresponding compound where Y is        CH₂;    -   (ii) into an acyl sulfonamide by coupling 3 with a sulfonamide        in the presence of a coupling agent such as DCC, or the like;    -   (iii) into a hydroxamic acid by coupling 3 with hydroxylamine in        the presence of a coupling agent such as T₃P, or the like.

Carboxylic acid 2 used for the coupling described in Scheme 1 may beprepared from ester 5 via its initial N-alkylation by an Ar—CH₂-LG (i.e.6) wherein LG is a leaving group such as halide, mesylate, tosylate, orthe like, in the presence of an appropriate base (i.e. NaH, Cs₂CO₃,KO^(t)Bu, or the like). Subsequent hydrolysis of ester 7 usingprocedures known to those skilled in the art including those describedabove provides the carboxylic acid 2.

Compound 6 is commercially available, or it may be conveniently preparedfrom the ester 8 by, for example, the initial reduction of 8 usingreagents such as DIBAL-H, LiBH₄, LiAlH₄, or the like (Scheme 3) to thecorresponding alcohol 9. Treatment of alcohol 9 with mesyl chloride,tosyl anhydride, PBr₃, or the like, in the presence of an appropriatebase such as NEt₃, pyridine, DABCO, or the like provides thecorresponding compound 6. Furthermore, reduction of 8 using deuteratedreducing agents such as LiAlD₄ allows access to analogues containingstable deuterium isotopes at the benzylic carbon of 9.

Alternatively, the ester intermediate 7 can be accessed via an initialarylation of amine 10 with ester 11 to provide the aniline ester 12,followed by a suitable annulation sequence (Scheme 4). Arylation of 10can be realized via direct S_(N)Ar displacement of an appropriatelyfunctionalized aryl fluoride (i.e. 11 where Hal=F) or viametal-catalyzed coupling of an appropriately functionalized aryl iodide(i.e. 11 where Hal=I). Annulation sequence can entail metal-catalyzedheterocyclization of the aniline nitrogen on ester 12 onto a pendantalkyne (i.e. 12 where FG=alkyne) to deliver the fused biaryl ester 7a,or acid-promoted condensation of intermediate ester 12 with formic acid,or the like, in the presence of a reducing metal (i.e. 12 where FG=NO₂)to deliver the fused biaryl ester 7b.

Amine 1 used for the coupling described in Scheme 1 may be prepared fromcarboxylic acid 13 (Scheme 5) via Curtius rearrangement (i.e. by way ofan acyl azide: 14 where FG=N₃), Hoffmann rearrangement (i.e. by way of aprimary amide: 14 where FG=NH₂), Lossen rearrangement (i.e. by way of ahydroxamic acid: 14 where FG=NHOH), or the like. The preparation of theprecursors for the rearrangement reactions (i.e. 14), as well asreagents and conditions for the rearrangement reactions, are well knownto those skilled in the art, and are described in standard textbookssuch as March's Advanced Organic Chemistry, 7^(th) Ed., John Wiley &Sons, 2013. The resulting product, carbamate 15, can be directlyde-protected to reveal the requisite amine 1 using conditions known tothose skilled in the art (i.e. by treatment with HCl, TFA, or the likewhen R is tert-butyl; or by hydrogenation in the presence of catalystssuch as Pd/C, Pt/C, or the like when R is benzyl). Alternatively, theremoval of the carbamate protecting group can be postponed until afterall the desired chemical manipulations of functional group(s) distal tothe nitrogen have been completed.

In instances where Ar of amide 16 (Scheme 6) is substituted with ahalogen such as Br or I, it may be deemed desirable to effect itstransformation into, for example, (hetero)aryl amide 17 or heterocyclicamide 18. Such functional group conversion can be readily realized usingmetal-catalyzed reactions known to those skilled in the art. Examples ofsuch conversions can include, but are not limited to: (a) Suzukireaction using (hetero)aryl boronic acid or (hetero)aryl boronate esteras the coupling partner, XPhos palladocycle, Pd(dppf)Cl₂ or any othersuitable palladium ligand complexes as the catalyst, and aqueouspotassium phosphate, sodium carbonate, or the like as the base; (b)Buchwald-Hartwig reaction using primary or secondary amine as thecoupling partner, RuPhos palladocycle, BrettPhos palladocycle or anyother suitable palladium ligand complexes as the catalyst, and sodiumtert-pentoxide, potassium tert-butoxide or the like as the base.

Preparation of Intermediates Intermediate acid 1:1-(4-cyanobenzyl)-1H-indole-7-carboxylic acid

To a solution of methyl 1H-indole-7-carboxylate (1 eq.) in DMF (0.29 M)cooled to 0° C.; was added potassium tert-butoxide (1.2 eq.) such thatthe reaction temperature does not exceed 5° C. The resulting suspensionwas stirred at 0° C.; for 30 min and then at RT for 30 min. The solutionwas re-cooled to 0° C.; and 4-(bromomethyl)benzonitrile (1.2 eq.) in DMF(0.69M) was added dropwise. The reaction mixture was allowed to warmslowly to RT over 16 h and then quenched with the addition of ice-waterand extracted with EtOAc. The combined organic extracts were washedfurther with water, 10% aq. NaHCO₃ and brine, dried over MgSO₄, andfiltered. Concentration of the filtrate in vacuo furnished the crudereaction product as a yellow viscous oil, which was purified by columnchromatography (SiO₂, gradient elution, 9:1 Hexane/EtOAc to EtOAc) toafford the product as a colorless oil that solidified upon standing (75%yield).

1-(4-cyanobenzyl)-1H-indole-7-carboxylic acid (1 eq.) was dissolved in a2:1 (v/v) solution (0.1 M) of THE and methanol. LiOH (5 eq., 2 N aq.solution) was added and the solution was heated at 50° C.; for 3 h. Thereaction mixture was cooled to RT and then neutralized with HCl (5 eq.,1 N aq. solution). The suspension was extracted with EtOAc. The combinedorganic extracts were washed further with water and brine, dried overMgSO₄, and filtered. Concentration of the filtrate in vacuo furnishedthe crude reaction product as a yellow viscous oil that solidified uponstanding. Trituration in toluene afforded the product as a white,crystalline solid (67% yield).

Intermediate acid 2:1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxylic acid

Prepared in an analogous fashion to Intermediate acid 1, but using1-(bromomethyl)-4-(trifluoromethyl)benzene (1.2 eq.) in place of4-(bromomethyl)benzonitrile.

Intermediate acid 3:1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxylicacid

Prepared in an analogous fashion to Intermediate acid 1, but usingmethyl 1H-pyrrolo[3,2-b]pyridine-7-carboxylate (1 eq.) in place ofmethyl 1H-indole-7-carboxylate; and1-(bromomethyl)-4-(trifluoromethyl)benzene (1.2 eq.) in place of4-(bromomethyl)benzonitrile.

Intermediate acid 4:1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxylicacid

Prepared in an analogous fashion to Intermediate acid 1, but usingmethyl 1H-pyrrolo[3,2-c]pyridine-7-carboxylate (1 eq.) in place ofmethyl 1H-indole-7-carboxylate; and1-(bromomethyl)-4-(trifluoromethyl)benzene (1.2 eq.) in place of4-(bromomethyl)benzonitrile.

Intermediate acid 5:1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxylicacid

Prepared in an analogous fashion to Intermediate acid 1, but usingmethyl 1H-pyrrolo[2,3-c]pyridine-7-carboxylate (1 eq.) in place ofmethyl 1H-indole-7-carboxylate; and1-(bromomethyl)-4-(trifluoromethyl)benzene (1.2 eq.) in place of4-(bromomethyl)benzonitrile.

Intermediate acid 6:1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxylic acid

A suspension of methyl 1H-indazole-7-carboxylate (1 eq.) and cesiumcarbonate (3 eq.) in DMF (0.74 M) was cooled to 0° C.; and1-(bromomethyl)-4-(trifluoromethyl)benzene (1.2 eq., 0.89M in DMF) wasadded dropwise. The reaction mixture was allowed to warm slowly to rtover 16 h and then quenched with ice-water and extracted with TBME. Thecombined organic extracts were washed further with water and brine,dried over MgSO₄, and filtered. Concentration of the filtrate in vacuofurnished the crude reaction product as a golden yellow oil, which waspurified with column chromatography (SiO₂, 9:1 (v/v) Hex:EtOAc to EtOAc)to afford the product as a colorless oil (76% yield).

The product from the previous step (1 eq.) was dissolved in a 3:2 (v/v)solution (0.11 M) of THF and methanol and LiOH (3 eq., 2 N aq. solution)was added. The resulting solution was stirred at RT for 16 h andneutralized with HCl (3 eq., 1 N aq. solution). The resulting suspensionwas extracted with EtOAc and the combined organic extracts were washedfurther with water and brine, dried over MgSO₄, and filtered.Concentration of the filtrate in vacuo furnished the crude reactionproduct as a viscous oil. Recrystallization from TBME and hexanesafforded the product as a white, crystalline solid (60% yield).

Intermediate acid 7:1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxylic acid

Methyl 2-fluoro-3-nitrobenzoate (1 eq.), (4-(trifluoromethyl)phenyl)methanamine (1.5 eq.) and potassium carbonate (2 eq.) were combined inDMF (0.24 M) and the suspension was heated at 80° C.; for 2 h. Thereaction was cooled to rt, diluted with EtOAc and washed sequentiallywith 10% aq. NH₄Cl, water and brine. The organic layer was then driedover MgSO₄ and filtered. Concentration of the filtrate in vacuofurnished the crude reaction product as a yellow semi-solid.Purification by column chromatography (SiO₂, 9:1 (v/v) Hex:EtOAc to 3:7(v/v) Hex:EtOAc) afforded methyl3-nitro-2-((4-(trifluoromethyl)benzyl)amino)benzoate as a golden, yellowoil (56% yield).

Methyl 3-nitro-2-((4-(trifluoromethyl)benzyl)amino)benzoate (1 eq.),iron powder (10 eq.) and ammonium chloride (10 eq.) were dissolved in a1:1 (v/v) solution (0.05 M) of 2-propanol and formic acid. The vesselwas tightly sealed and heated at 80° C.; for 3 h. The suspension wascooled to rt, diluted with 2-propanol and filtered through celite. Thefiltrate was concentrated in vacuo and the resulting residue was takenup in DCM. The solution was then washed sequentially with 1 N aq. NaOH,water and brine, dried over MgSO₄, and filtered. Concentration of thefiltrate in vacuo furnished the crude reaction product as an orange oil.Purification by column chromatography (SiO₂, 9:1 (v/v) Hex:EtOAc toEtOAc) afforded methyl 1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxylate as an orange oil (31% yield).

Methyl 1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxylate(1 eq.) was dissolved in a 2:1 (v/v) solution (0.04 M) of THF andmethanol and LiOH was added (3 eq., 2 N aq. solution). The solution wasstirred at rt for 16 h and then neutralized with HCl (3 eq., 1 N aq.solution). The volatiles were removed in vacuo and the solid residue wastriturated in water to afford1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxylic acid asa white, crystalline solid (58% yield).

Intermediate acid 8:1-((4-(trifluoromethyl)phenyl)-methyl-d₂)-1H-indole-7-carboxylic acid

Methyl 4-(trifluoromethyl)benzoate (1 eq.) was dissolved in THF (0.3 M)and cooled to 0° C. Lithium aluminum deuteride (1 eq.) was added and theresulting suspension was warmed slowly to rt over 16 h. The reaction wascooled to 0° C.; and quenched with 1 N aq. HCl and then extracted withDCM. The combined organic extracts were then washed further with waterand brine, dried over MgSO₄ and filtered. Concentration of the filtratein vacuo furnished the crude reaction product as a colorless oil.Purification by column chromatography (SiO₂, Hex to 3:7 (v/v) Hex:EtOAc)afforded (4-(trifluoromethyl)phenyl)-methan-d₂-ol as a colorless oil(61% yield).

(4-(trifluoromethyl)phenyl)-methan-d₂-ol (1 eq.) and triethylamine (1.5eq.) were combined in DCM (0.39 M), cooled to 0° C., and methanesulfonylchloride (1.2 eq.) was added dropwise. The resulting solution stirred at0° C.; for 30 min and then at rt for 1.5 h. The reaction mixture wasthen diluted with TBME and washed sequentially with water, 1 N aq. NaOH,1 N aq. HCl, water and finally brine. The organic extract was then driedover MgSO₄ and filtered. Concentration of the filtrate in vacuofurnished the desired crude((4-(trifluoromethyl)phenyl)-methyl-d₂)-methanesulfonate as a colorlessoil (>99% yield).

Methyl 1H-indole-7-carboxylate (1 eq.) was dissolved in DMF (0.32 M) andcooled to 0° C. Potassium tert-butoxide (1.2 eq.) was added over 20 minsuch that the internal reaction temperature does not exceed 5° C. Theresulting suspension was stirred at 0° C.; for 30 min, at rt for 30 min,then cooled back to 0° C.((4-(trifluoromethyl)phenyl)-methyl-d₂)-methanesulfonate (1.2 eq.) fromthe previous step was added dropwise as a DMF (0.2 M) solution. Theresulting reaction mixture was warmed slowly to rt over 16 h and thenquenched with deuterium oxide and extracted with EtOAc. The combinedorganic extracts were washed further with water, 10% aq. NaHCO₃ andbrine, dried over MgSO₄, and filtered. Concentration of the filtrate invacuo furnished the crude reaction product as a viscous oil.Purification by column chromatography (SiO₂, 9:1 (v/v) Hex: EtOAc toEtOAc) afforded methyl1-((4-(trifluoromethyl)phenyl)-methyl-d₂)-1H-indole-7-carboxylate as acolorless oil (59% yield).

Methyl 1-((4-(trifluoromethyl)phenyl)-methyl-d₂)-1H-indole-7-carboxylate(1 eq.) was dissolved in a 2:1 (v/v) solution (0.1 M) of THF andmethanol and LiOH (3 eq., 2 N aq. solution) was added. The resultingsolution was heated at 50° C.; for 3 h, cooled to rt and thenneutralized with HCl (3 eq., 1 N aq. solution). The resulting suspensionwas filtered and the solid cake rinsed with a cold 1:1 (v/v) solution ofmethanol and water. The product1-((4-(trifluoromethyl)phenyl)-methyl-d₂)-1H-indole-7-carboxylic acidwas dried in vacuo for 16 h, providing a crystalline solid (61% yield).

Intermediate acid 9:4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxylic acid

Prepared in an analogous fashion to Intermediate acid 1, but usingmethyl 4-fluoro-1H-indole-7-carboxylate (1 eq.) in place of methyl1H-indole-7-carboxylate; and 1-(bromomethyl)-4-(trifluoromethyl)benzene(1.2 eq.) in place of 4-(bromomethyl)benzonitrile.

Intermediate acid 10:5-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxylic acid

Prepared in an analogous fashion to Intermediate acid 1, but usingmethyl 5-fluoro-1H-indole-7-carboxylate (1 eq.) in place of methyl1H-indole-7-carboxylate; and 1-(bromomethyl)-4-(trifluoromethyl)benzene(1.2 eq.) in place of 4-(bromomethyl)benzonitrile.

Intermediate acid 11:5-chloro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxylic acid

Prepared in an analogous fashion to Intermediate acid 1, but usingmethyl 5-chloro-1H-indole-7-carboxylate (1 eq.) in place of methyl1H-indole-7-carboxylate; and 1-(bromomethyl)-4-(trifluoromethyl)benzene(1.2 eq.) in place of 4-(bromomethyl)benzonitrile.

Intermediate acid 12:6-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxylic acid

Prepared in an analogous fashion to Intermediate acid 1, but usingmethyl 6-fluoro-1H-indole-7-carboxylate (1 eq.) in place of methyl1H-indole-7-carboxylate; and 1-(bromomethyl)-4-(trifluoromethyl)benzene(1.2 eq.) in place of 4-(bromomethyl)benzonitrile.

Intermediate acid 13:1-(4-(difluoromethyl)benzyl)-1H-indole-7-carboxylic acid

Prepared in an analogous fashion to Intermediate acid 1, but using1-(chloromethyl)-4-(difluoromethyl)benzene (1.2 eq.) in place of4-(bromomethyl)benzonitrile.

Intermediate acid 14:1-(4-(difluoromethyl)benzyl)-4-fluoro-1H-indole-7-carboxylic acid

Prepared in an analogous fashion to Intermediate acid 1, but usingmethyl 4-fluoro-1H-indole-7-carboxylate (1 eq.) in place of methyl1H-indole-7-carboxylate; and 1-(chloromethyl)-4-(difluoromethyl)benzene(1.2 eq.) in place of 4-(bromomethyl)benzonitrile.

Intermediate acid 15:1-(4-(pentafluoro-λ⁶-sulfaneyl)benzyl)-1H-indole-7-carboxylic acid

Prepared in an analogous fashion to Intermediate acid 1, but using4-(pentafluorothio)benzyl bromide (1.2 eq.) in place of4-(bromomethyl)benzonitrile.

Intermediate acid 16:1-([1,1′-biphenyl]-4-ylmethyl)-1H-indole-7-carboxylic acid

Prepared in an analogous fashion to Intermediate acid 1, but using4-(bromomethyl)-1,1′-biphenyl (1.2 eq.) in place of4-(bromomethyl)benzonitrile.

Intermediate acid 17:1-([1,1′-biphenyl]-4-ylmethyl)-4-fluoro-1H-indole-7-carboxylic acid

Prepared in an analogous fashion to Intermediate acid 1, but usingmethyl 4-fluoro-1H-indole-7-carboxylate (1 eq.) in place of methyl1H-indole-7-carboxylate; and 4-(bromomethyl)-1,1′-biphenyl (1.2 eq.) inplace of 4-(bromomethyl)benzonitrile.

Intermediate acid 18:1-([1,1′-biphenyl]-4-ylmethyl)-1H-indazole-7-carboxylic acid

Prepared in an analogous fashion to Intermediate acid 6, but using4-(bromomethyl)-1,1′-biphenyl (1.2 eq.) in place of1-(bromomethyl)-4-(trifluoromethyl)benzene.

Intermediate acid 19:1-(4-(trifluoromethoxy)benzyl)-1H-indazole-7-carboxylic acid

Prepared in an analogous fashion to Intermediate acid 6, but using1-(bromomethyl)-4-(trifluoromethoxy)benzene (1.2 eq.) in place of1-(bromomethyl)-4-(trifluoromethyl)benzene.

Intermediate acid 20: 4-fluoro-1-(4-iodobenzyl)-1H-indole-7-carboxylicacid

Prepared in an analogous fashion to Intermediate acid 1, but usingmethyl 4-fluoro-1H-indole-7-carboxylate (1 eq.) in place of methyl1H-indole-7-carboxylate; and 1-(bromomethyl)-4-iodobenzene (1.2 eq.) inplace of 4-(bromomethyl)benzonitrile.

Intermediate Amine 1: ethyl 2-(3-aminobicyclo[1.1.1]pentan-1-yl)acetatehydrochloride

3-(methoxycarbonyl)bicyclo[1.1.1]pentan-1-carboxylic acid (1 eq.) wasdissolved in tert-butanol (0.25 M) and triethylamine (1 eq.) anddiphenylphosphoryl azide (1.5 eq.) were added sequentially. Theresulting solution was stirred at RT for 1 h and then heated at 80° C.;for 22 h. The volatiles were then removed in vacuo and the resultingresidue was taken up in EtOAc. The organic layer was then washedsequentially with water and brine, dried over MgSO₄, and filtered.Concentration of the filtrate in vacuo furnished the crude reactionproduct as a viscous oil. Purification by column chromatography (SiO₂,9:1 (v/v) Hex: EtOAc to 1:1 (v/v) Hex: EtOAc) afforded methyl3-((tert-butoxycarbonyl)amino bicyclo[1.1.1]pentan-1-carboxylate as awhite, crystalline solid (79% yield).

Methyl 3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-carboxylate(1 eq.) was dissolved in THF (0.13 M), the solution cooled to 0° C.; andLiBH₄ (10 eq., 1 M THF solution) was added dropwise. The resultingmixture was warmed slowly to rt over 18 h, quenched with 10% aq. NH₄Cland the volatiles were removed in vacuo. The resulting aqueous residuewas then diluted further with water and extracted with EtOAc and Me-THF.The combined organic extracts were then washed further with water andbrine, dried over MgSO₄, filtered and the filtrate concentrated invacuo. Purification by column chromatography (SiO₂, 9:1 (v/v) Hex: EtOActo 3:7 (v/v) Hex: EtOAc) afforded tert-butyl(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate as a white,crystalline solid (78% yield).

tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (1 eq.)and triethylamine (1.5 eq.) were combined in DCM (0.21 M), cooled to 0°C., and methanesulfonyl chloride (1.2 eq.) was added dropwise. Theresulting solution stirred at 0° C.; for 30 min and then at rt for 18 h.The reaction mixture was then diluted with EtOAc and washed sequentiallywith water and brine. The organic extract was then dried over MgSO₄ andfiltered. Concentration of the filtrate in vacuo furnished the desiredcrude (3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methylmethanesulfonate as a white crystalline solid (99% yield).

(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)methylmethanesulfonate (1 eq.) and KCN (2 eq.) were combined in DMF (0.075 M)and heated at 70° C.; for 24 h. The crude reaction mixture was cooled tort, diluted with TBME, and washed sequentially with water and brine. Theorganic extract was then dried over MgSO₄ and filtered. Concentration ofthe filtrate in vacuo furnished the crude tert-butyl(3-(cyanomethyl)bicyclo[1.1.1]pentan-1-yl)carbamate as a pale yellow oil(92% yield).

tert-butyl (3-(cyanomethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (1 eq.)was dissolved in ethanol (0.14 M) and bubbled with gaseous HCl (withcooling) for 10 min. The reaction vessel was then tightly sealed andheated at 75° C.; for 48 h, and then cooled to rt and carefully vented.Water (10 eq.) was added, and the reaction mixture was stirred at rt for3 h. The volatiles were removed in vacuo and the resulting residue wastriturated in ethanol and DCM for 30 min, filtered, and the filtrate wasthen concentrated in vacuo to furnish the desired, crude ethyl2-(3-aminobicyclo[1.1.1]pentan-1-yl)acetate hydrochloride as ahygroscopic solid (93% yield).

Intermediate Amine 2:2-(3-(chloro-λ⁵-azaneyl)bicyclo[1.1.1]pentan-1-yl)acetonitrile

tert-butyl (3-(cyanomethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (1 eq.,Intermediate amine 1, Step 4) was dissolved in DCM (0.071 M), cooled to0° C., and HCl (30 eq., 4 M dioxane solution) was added dropwise. Theresulting solution was stirred at 0° C.; for 30 min and then at rt for 2h. The volatiles were removed in vacuo to furnish the title compound asa pale yellow foam (99% yield).

Intermediate Amine 3: ethyl 2-(4-aminobicyclo[2.1.1]hexan-1-yl)acetatehydrochloride

4-((tert-butoxycarbonyl)amino)bicyclo[2.1.1]hexane-1-carboxylic acid (1eq.) and triethylamine (1.5 eq.) were dissolved in THE (0.22 M), cooledto −15° C., and ethyl chloroformate (1.5 eq.) was added dropwise. Theresulting mixture was stirred at −15° C.; for 3 h, diluted with TBME andwashed sequentially with water and brine. The organic extract was thendried over MgSO₄, filtered and the filtrate concentrated in vacuo. Thecrude mixed anhydride intermediate was taken up in methanol (0.22 M),cooled to 0° C., and LiBH₄ (6 eq.) was added portion-wise over a periodof 30 min. The resulting mixture was warmed slowly to rt over 16 h andquenched with 10% aq. NH₄Cl. The volatiles were removed in vacuo, andthe resulting aqueous residue was diluted further with water andextracted with EtOAc. The combined organic extracts were then washedfurther with water and brine, dried over MgSO₄, filtered and thefiltrate concentrated in vacuo. Purification by column chromatography(SiO₂, 9:1 (v/v) Hex: EtOAc to 3:7 (v/v) Hex: EtOAc) afforded tert-butyl(4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)carbamate as a white,crystalline solid (88% yield).

tert-butyl (4-(hydroxymethyl)bicyclo[2.1.1]hexan-1-yl)carbamate (1 eq.)and triethylamine (1.5 eq.) were combined in DCM (0.13 M), cooled to 0°C., and methanesulfonyl chloride (1.2 eq.) was added dropwise. Theresulting solution was stirred at 0° C.; for 30 min and at rt for 18 h,diluted with EtOAc and washed sequentially with water and brine. Theorganic extract was dried over MgSO₄ and filtered. Concentration of thefiltrate in vacuo furnished crude4-(((tert-butoxycarbonyl)amino)bicyclo[2.1.1]hexan-1-yl)methylmethanesulfonate as a white crystalline solid (99% yield).

(4-((tert-butoxycarbonyl)amino)bicyclo[2.1.1]hexan-1-yl)methylmethanesulfonate (1 eq.) and KCN (2 eq.) were combined in DMF (0.055 M)and heated at 80° C.; for 24 h. The crude reaction mixture was cooled tort, diluted with TBME, and washed sequentially with water and brine. Theorganic extract was then dried over MgSO₄ and filtered. Concentration ofthe filtrate in vacuo furnished crude tert-butyl(4-(cyanomethyl)bicyclo[2.1.1]hexan-1-yl)carbamate as a pale yellow oil(99% yield).

tert-butyl (4-(cyanomethyl)bicyclo[2.1.1]hexan-1-yl)carbamate (1 eq.)was dissolved in ethanol (0.05 M), and gaseous HCl was bubbled in withcooling for 10 min. The reaction vessel was tightly sealed and heated at80° C.; for 48 h, cooled to rt and carefully vented. Water (10 eq.) wasadded and the mixture was stirred at rt for 2 h. The volatiles wereremoved in vacuo and the resulting residue was triturated in ethanol andDCM for 30 min, filtered, and the filtrate concentrated in vacuo tofurnish the desired, crude product as a hygroscopic solid (96% yield).

EXAMPLES

While preferred embodiments of the present disclosure have been shownand described herein, it will be obvious to those skilled in the artthat such embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the present disclosure. It should beunderstood that various alternatives to the embodiments of the presentdisclosure described herein may be employed in practicing the presentdisclosure. It is intended that the following claims define the scope ofthe present disclosure and that methods and structures within the scopeof these claims and their equivalents be covered thereby.

Example 1:2-(3-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid

Step 1: ethyl 2-(3-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetate: Intermediate acid 1 (1 eq.), Intermediateamine 1 (1.5 eq.) and HATU (1.5 eq.) were dissolved in DMF (0.09 M). Tothis was then added ethyl-diisopropyl-amine (3 eq.) and the resultingyellow solution was allowed to stir at RT for 18 h. The crude reactionmixture was diluted with EtOAc and washed sequentially with water, 10%aq. NaHCO₃, 10% aq. NH₄Cl, water and brine. The organic extract wasdried over MgSO₄, filtered and the filtrate concentrated in vacuo.Further purification by column chromatography (SiO₂, 1:1 (v/v) Hex:EtOAc to EtOAc) furnished the product as a pale yellow solid (54%yield).

Step 2: 2-(3-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid: Ethyl2-(3-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetate(1 eq.) from the previous step was dissolved in a 2:1 (v/v) solution(0.02 M) of THE and methanol, LiOH (5 eq., 2 N aq. solution) was addedand the resulting solution was heated at 50° C.; for 4 h. The reactionmixture was cooled to RT and then neutralized with HCl (5 eq., 1 N aq.solution). The volatiles were then removed in vacuo and the resultingresidue was directly subjected to reverse-phase column chromatography(C₁₈, 9:1 (v/v) H₂O: MeCN+0.1% formic acid to MeCN+0.1% formic acid).Fractions with the product were combined and concentrated in vacuo. Theresulting aqueous suspension was then neutralized with sat. aq. NaHCO₃and extracted with EtOAc. The combined organic extracts were washedfurther with water and brine, dried over MgSO₄, and filtered.Concentration of the filtrate in vacuo afforded, after a furthertrituration in toluene, the product as a white, crystalline solid (77%yield). ESI⁺: M+1: 400. ESI⁻: M−1: 398.

Example 2:2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)aceticacid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 2 (1 eq.) in place of Intermediate acid 1 in Step 1. ESI⁺: M+1:443. ESI⁻: M−1: 441.

Example 3:2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 3 (1 eq.) in place of Intermediate acid 1 in Step 1. ESI⁺: M+1:444. ESI⁻: M−1: 442.

Example 4:2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid

Prepare in an analogous fashion to Example 1, but using Intermediateacid 4 (1 eq.) in place of Intermediate acid 1 in Step 1. ESI⁺: M+1:444. EST: M−1: 442.

Example 5:2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 5 (1 eq.) in place of Intermediate acid 1 in Step 1. ESI⁺: M+1:444. ESI⁻: M−1: 442.

Example 6:2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)aceticacid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 6 (1 eq.) in place of Intermediate acid 1 in Step 1. ESI⁺: M+1:444. ESI⁻: M−1: 442.

Example 7:2-(3-(1-((4-(trifluoromethyl)phenyl)methyl-d₂)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 8 (1 eq.) in place of Intermediate acid 1 in Step 1. ESI⁺: M+1:445. ESI⁻: M−1: 443.

Example 8:(R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid and(S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid (enantiomer 8a and enantiomer 8b)

Prepared in an analogous fashion to Example 1, but using Intermediateacid 2 (1 eq.) in place of Intermediate acid 1 and rac-methyl6-aminospiro[3.3]heptane-2-carboxylate hydrochloride (1.5 eq.) in placeof Intermediate amine 1 in Step 1. The racemic product from Step 2 wasfurther resolved by chiral SFC (stationary phase: AD 10×250 mm, 5 μm;mobile phase: 25% methanol, 100 Bar of CO₂; column temperature: 35° C.;flow rate: 10 mL/min) into its two enantio-enriched (>99% e.e.)antipodes. First eluting enantiomer; RT: 3.16 min, ESI⁺: M+1: 457. ESI⁻:M−1: 455. Second eluting enantiomer; RT: 5.32 min, ESI⁺: M+1: 457. ESI⁻:M 1: 455.

Example 9:rac-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 3 (1 eq.) in place of Intermediate acid 1 and rac-methyl6-aminospiro[3.3]heptane-2-carboxylate hydrochloride (1.5 eq.) in placeof Intermediate amine 1 in Step 1. ESI⁺: M+1: 458. ESI⁻: M−1: 456.

Example 10:(R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylic acid and(S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylic acid (enantiomer 10a and enantiomer 10b)

Prepared in an analogous fashion to Example 1, but using Intermediateacid 4 (1 eq.) in place of Intermediate acid 1 and rac-methyl6-aminospiro[3.3]heptane-2-carboxylate hydrochloride (1.5 eq.) in placeof Intermediate amine 1 in Step 1. ESI⁺: M+1: 458. ESI⁻: M−1: 456. Theracemic product from Step 2 was further resolved by chiral SFC(stationary phase: OJ 10×250 mm, 5 μm; mobile phase: 25% methanol, 100Bar of CO₂; column temperature: 35° C.; flow rate: 10 mL/min) into itstwo enantio-enriched (>99% e.e.) antipodes. First eluting enantiomer;RT: 3.10 min, ESI⁺: M+1: 458. ESI⁻: M−1: 456. Second eluting enantiomer;RT: 4.60 min, ESI⁺: M+1: 458. ESI⁻: M−1: 456.

Example 11:rac-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 5 (1 eq.) in place of Intermediate acid 1 and rac-methyl6-aminospiro[3.3]heptane-2-carboxylate hydrochloride (1.5 eq.) in placeof Intermediate amine 1 in Step 1. ESI⁺: M+1: 458. ESI⁻: M−1: 456.

Example 12:rac-6-(1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 6 (1 eq.) in place of Intermediate acid 1 and rac-methyl6-aminospiro[3.3]heptane-2-carboxylate hydrochloride (1.5 eq.) in placeof Intermediate amine 1 in Step 1. ESI⁺: M+1: 458. ESI⁻: M−1: 456.

Example 13:rac-6-(1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxamido)spiro[3.3]heptane-2-carboxylic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 7 (1 eq.) in place of Intermediate acid 1 and rac-methyl6-aminospiro[3.3]heptane-2-carboxylate hydrochloride (1.5 eq.) in placeof Intermediate amine 1 in Step 1. ESI⁺: M+1: 458. ESI⁻: M−1: 456.

Example 14:3-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)propanoicacid Example 15:cis-3-(3-methyl-3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)cyclobutyl)propanoic acid

Step 1: tert-butyl (3-formylbicyclo[1.1.1]pentan-1-yl)carbamate:tert-butyl (3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)carbamate (1 eq.,Intermediate amine 1, Step 2) and sodium bicarbonate (1.5 eq.) weresuspended in DCM (0.034 M). Dess-Martin periodinane (1.2 eq.) was addedto the reaction mixture and stirred at RT for 1.5 h. The reactionmixture was then diluted with TBME and washed sequentially with 10% aq.Na₂S₂O₃, 1 N aq. NaOH, water and brine. The organic extract was thendried over MgSO₄ and filtered. Concentration of the filtrate in vacuofurnished the desired crude product as a white crystalline solid (68%yield).

Step 2: (E)-methyl 3-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)acrylate: tert-butyl(3-formylbicyclo[1.1.1]pentan-1-yl)carbamate (1 eq.) from the previousstep was dissolved in THE (0.034 M) and methyl2-(triphenylphosphoranylidene)acetate (1 eq.) was added. The resultingsolution was stirred at RT for 18 h and then diluted with TBME andwashed sequentially with 1 N aq. HCl, water and brine. The organicextract was then dried over MgSO₄ and filtered. Concentration of thefiltrate in vacuo furnished the crude reaction product as a viscous oil.Further purification by way of column chromatography (SiO₂, 9:1 (v/v)Hex:EtOAc to 3:7 (v/v) Hex:EtOAc) afforded the product as a colorlessoil (94% yield).

Step 3: methyl3-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)propanoateand cis-methyl 3-(3-((tert-butoxycarbonyl)amino)-3-methylcyclobutyl)propanoate: (E)-methyl3-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)acrylate (1eq.) from the previous step and palladium (0.06 eq., 10% (w/w) overcarbon, dry) were mixed in a 1:1 (v/v) solution (0.032 M) of methanoland EtOAc. The resulting suspension was then de oxygenated with nitrogenfor 10 min and the reaction vessel was evacuated and back-filled withhydrogen and stirred at RT under a balloon of hydrogen for 2 h. Thereaction was then quenched with DCM and the resulting suspension wasfiltered through celite. Concentration of the filtrate in vacuofurnished a 1.7:1 mixture of methyl3-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)propanoateand cis-methyl3-(3-((tert-butoxycarbonyl)amino)-3-methylcyclobutyl)propanoate as awhite foam (81% yield).

Step 4: methyl 3-(3-aminobicyclo[1.1.1]pentan-1-yl)propanoatehydrochloride and cis-methyl 3-(3-amino-3-methylcyclobutyl)propanoatehydrochloride: The mixture of methyl3-(3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentan-1-yl)propanoateand cis-methyl3-(3-((tert-butoxycarbonyl)amino)-3-methylcyclobutyl)propanoate (1 eq.)from the previous step was dissolved in DCM (0.051 M) and HCl (10 eq., 4M dioxane solution) was added dropwise at 0° C. The resulting solutionwas stirred at 0° C.; for 30 min and then at RT for 4 h. The volatileswere then evaporated in vacuo to furnish a 1.7:1 mixture of methyl3-(3-aminobicyclo[1.1.1]pentan-1-yl)propanoate hydrochloride andcis-methyl 3-(3-amino-3-methylcyclobutyl)propanoate hydrochloride as awhite foam (99% yield).

Step 5: methyl3-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)propanoateand cis-methyl3-(3-methyl-3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)cyclobutyl)propanoate:Intermediate acid 2 (1 eq.), the mixture of methyl3-(3-aminobicyclo[1.1.1]pentan-1-yl)propanoate hydrochloride andcis-methyl 3-(3-amino-3-methylcyclobutyl)propanoate hydrochloride (1.5eq.) from the previous step, and HATU (1.5 eq.) were dissolved in DMF(0.13 M). Ethyl-diisopropyl-amine (3 eq.) was added and the resultingsolution stirred at RT for 18 h. The crude reaction mixture was dilutedwith EtOAc and washed sequentially with water, 10% aq. NaHCO₃, 10% aq.NH₄Cl, water and brine. The organic extract was then dried over MgSO₄,filtered and the filtrate concentrated in vacuo. Purification by columnchromatography (SiO₂, 1:1 (v/v) Hex: EtOAc to EtOAc) furnished a 1.7:1mixture of methyl3-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)propanoateand cis-methyl3-(3-methyl-3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)cyclobutyl)propanoate as a pale yellow foam (67% yield).

Step 6:3-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)propanoicacid andcis-3-(3-methyl-3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)cyclobutyl)propanoicacid: The mixture of methyl3-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)propanoate and cis-methyl3-(3-methyl-3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)cyclobutyl)propanoate(1 eq.) from the previous step were dissolved in a 2:1 (v/v) solution(0.057 M) of THE and methanol and LiOH (3 eq., 2 N aq. solution) wasadded. The resulting solution was stirred at RT for 16 h and neutralizedwith HCl (3 eq., 1 N aq. solution). The volatiles were then removed invacuo and the resulting residue was directly subjected to purificationby way of chiral SFC (stationary phase: AD 10×250 mm, 5 μm; mobilephase: 25% methanol, 100 Bar of CO₂; column temperature: 35° C.; flowrate: 10 mL/min). Second eluting peak:3-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)propanoicacid, Example 14, ESI⁺: M+1: 459. EST: M 1: 457. First eluting peak:cis-3-(3-methyl-3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)cyclobutyl)propanoicacid, Example 15, ESI⁺: M+1: 459. ESI⁻: M−1: 457.

Example 16:N-(3-(2-oxo-2-(phenylsulfonamido)ethyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide

2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid (1 eq., Example 2), EDCI (1.4 eq.),benzenesulfonamide (1.4 eq.) and DMAP (1.4 eq.) were combined in DCM(0.019 M). Ethyl-diisopropyl-amine (1.4 eq.) was added and the resultingsolution was stirred at RT for 18 h. The reaction mixture was thendiluted with EtOAc and washed sequentially with 1 N aq. HCl, water andbrine. The organic extract was then dried over MgSO₄ and filtered.Concentration of the filtrate in vacuo furnished the crude reactionproduct as an off-white solid. Further purification by columnchromatography (SiO₂, 9:1 (v/v) Hex:EtOAc to EtOAc to 10:1 (v/v)EtOAc:MeOH) afforded the title compound as a white powder (30% yield).ESI⁺: M+1: 582. ESI⁻: M−1: 580.

Example 17:N-(3-((3-(phenylsulfonyl)ureido)methyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide

Step 1: methyl3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentane-1-carboxylate:Intermediate acid 2 (1 eq.), methyl3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride (1.5 eq.) andHATU (1.5 eq.) were dissolved in DMF (0.09 M) andethyl-diisopropyl-amine (3 eq.) was added. The resulting solutionstirred at RT for 18 h, diluted with EtOAc and washed sequentially withwater, 10% aq. NaHCO₃, 10% aq. NH₄Cl, water and brine. The organicextract was then dried over MgSO₄, filtered and the filtrateconcentrated in vacuo. Purification by column chromatography (SiO₂, 1:1(v/v) Hex:EtOAc to EtOAc) furnished the product as a pale yellow solid(71% yield).

Step 2: 3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentane-1-carboxylic acid: methyl3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentane-1-carboxylate(1 eq.) from the previous step was dissolved in a 2:1 (v/v) solution(0.03 M) of THF and methanol and LiOH (5 eq., 2 N aq. solution) wasadded. The resulting solution was stirred at 50° C.; for 18 h, cooled toRT and neutralized with HCl (5 eq., 1 N aq. solution). The volatileswere then removed in vacuo and the resulting residue was directlysubjected to reverse-phase column chromatography (C₁₈, 9:1 (v/v)H₂O:MeCN+0.1% formic acid to MeCN+0.1% formic acid). Fractions with theproduct were combined and concentrated in vacuo. The resulting aqueoussuspension was then neutralized with the addition of sat. aq. NaHCO₃ andextracted with EtOAc. The combined organic extracts were washed furtherwith water and brine, dried over MgSO₄, and filtered. Concentration ofthe filtrate in vacuo afforded the product as a white, crystalline solid(55% yield).

Step 3:N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide:3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentane-1-carboxylicacid (1 eq.) from the previous step and triethylamine (1.5 eq.) weredissolved in THF (0.12 M), the solution was cooled to −15° C.; and ethylchloroformate (1.5 eq.) was added dropwise. The reaction mixture wasstirred at −15° C.; for 3 h, diluted with TBME and washed sequentiallywith water and brine. The organic extract was then dried over MgSO₄,filtered and the filtrate concentrated in vacuo. The crude mixedanhydride intermediate was taken up in methanol (0.12 M) and LiBH₄ (6eq.) was added at 0° C. The resulting mixture was then warmed slowly toRT over 16 h, quenched with 10% aq. NH₄Cl and the volatiles were removedin vacuo. The resulting aqueous residue was then diluted further withwater and extracted with EtOAc. The combined organic extracts werewashed further with water and brine, dried over MgSO₄, filtered and thefiltrate concentrated in vacuo. Purification by column chromatography(SiO₂, 4:1 (v/v) Hex:EtOAc to EtOAc) afforded the product as a whitefoam (60% yield).

Step 4: (3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)methyl methanesulfonate:N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide(1 eq.) from the previous step and triethylamine (1.5 eq.) weredissolved in DCM (0.087 M) and methanesulfonyl chloride (1.2 eq.) wasadded dropwise at 0° C. The resulting solution was stirred at 0° C.; for30 min and then at RT for 18 h. The reaction mixture was then dilutedwith EtOAc and washed sequentially with water and brine. The organicextract was then dried over MgSO₄ and filtered. Concentration of thefiltrate in vacuo furnished the desired crude product as a pale yellowfoam (89% yield).

Step 5:N-(3-(azidomethyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide:(3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)methylmethanesulfonate (1 eq.) from the previous step and sodium azide (2 eq.)were combined in DMF (0.12 M) and heated at 80° C.; for 24 h. The crudereaction mixture was then cooled to RT, diluted with EtOAc, and washedsequentially with water and brine. The organic extract was then driedover MgSO₄, filtered and the filtrate concentrated in vacuo.Purification by column chromatography (SiO₂, 4:1 (v/v) Hex:EtOAc toEtOAc) afforded the product as a white, crystalline solid (47% yield).

Step 6:N-(3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide:N-(3-(azidomethyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide(1 eq.) from the previous step and triphenylphosphine (1.5 eq.) werecombined in a 3:1 (v/v) solution (0.028 M) of THE and water. Theresulting mixture was heated at 45° C.; for 48 h, cooled to RT anddirectly subjected to purification by rpHPLC (C₁₈, 9:1 (v/v) H₂O:MeCN+0.1% formic acid to MeCN+0.1% formic acid). Fractions with theproduct were combined and concentrated in vacuo. The resulting aqueoussuspension was then neutralized with 1 N aq. NaOH and extracted withDCM. The combined organic extracts were washed further with water andbrine, dried over MgSO₄, and filtered. Concentration of the filtrate invacuo afforded the product as a colorless oil (77% yield).

Step 7:N-(3-((3-(phenylsulfonyl)ureido)methyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide:N-(3-(aminomethyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide(1 eq.) from the previous step was dissolved in DCM (0.042 M) andbenzenesulfonyl isocyanate (1.1 eq.) was added. The resulting mixturewas stirred at RT for 18 h, the volatiles were removed in vacuo and theresulting residue was directly subjected to purification by rpHPLC (C₁₈,9:1 (v/v) H₂O: MeCN+0.1% formic acid to MeCN+0.1% formic acid).Fractions with the product were combined and concentrated in vacuo toafford the title compound as a white foam (52% yield). ESI⁺: M+1: 597.ESI⁻: M−1: 595.

Example 18:N-(3-((1H-tetrazol-5-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide

Step 1:N-(3-(cyanomethyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide:Intermediate acid 2 (1 eq.), Intermediate amine 2 (1.5 eq.) and HATU(1.5 eq.) were dissolved in DMF (0.55 M). and ethyl-diisopropyl-amine (3eq.) was added. The resulting solution was stirred at RT for 18 h,diluted with TBME and washed sequentially with water, 1 N aq. NaOH,water and brine. The organic extract was then dried over MgSO₄, filteredand the filtrate concentrated in vacuo. Purification by columnchromatography (SiO₂, 9:1 (v/v) Hex:EtOAc to EtOAc) furnished theproduct as a white, crystalline solid (62% yield).

Step 2:N-(3-((1H-tetrazol-5-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide:N-(3-(cyanomethyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide (1eq.) from the previous step, sodium azide (2 eq.) and dibutyltin(IV)oxide (0.1 eq.) were combined in a 1:1 (v/v) solution (0.052 M) of NMPand water. The reaction vessel was tightly sealed and heated behind ablast shield at 110° C.; for 1 week. The resulting mixture was cooled toRT and then directly subjected to rpHPLC (C₁₈, 9:1 (v/v) H₂O: MeCN+0.1%formic acid to MeCN+0.1% formic acid). Fractions with the product werecombined and concentrated in vacuo to afford the title compound as awhite foam (45% yield). ESI⁺: M+1: 467. ESI⁻: M−1: 465.

Example 19:2-(4-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[2.1.1]hexan-1-yl)aceticacid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 2 (1 eq.) in place of Intermediate acid 1 and intermediate amine 3(1.5 eq.) in place of in intermediate amine 1 in Step 1. ESI⁺: M+1: 457.ESI⁻: M−1: 455.

Example 20:(R)-6-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid and(S)-6-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic acid (enantiomer 20a and enantiomer 20b)

Prepared in an analogous fashion to Example 1, but using Intermediateacid 9 (1 eq.) in place of Intermediate acid 1 and rac-methyl6-aminospiro[3.3]heptane-2-carboxylate hydrochloride (1.5 eq.) in placeof Intermediate amine 1 in Step 1. ESI⁺: M+1: 475. ESI⁻: M−1: 473. Theracemic product from Step 2 was further resolved by chiral SFC(stationary phase: AD 10×250 mm, 5 μm; mobile phase: 20% methanol, 100Bar of CO₂; column temperature: 35° C.; flow rate: 10 mL/min) into itstwo enantio-enriched (>99% e.e.) antipodes. First eluting enantiomer;RT: 3.96 min, ESI⁺: M+1: 475. ESI⁻: M−1: 473. Second eluting enantiomer;RT: 7.66 min, ESI⁺: M+1: 475. ESI⁻: M−1: 473.

Example 21:rac-6-(5-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiroheptane-2-carboxylic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 10 (1 eq.) in place of Intermediate acid 1 and rac-methyl6-aminospiro[3.3]heptane-2-carboxylate hydrochloride (1.5 eq.) in placeof Intermediate amine 1 in Step 1. ESI⁺: M+1: 475. ESI⁻: M−1: 473.

Example 22:rac-6-(5-chloro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiroheptane-2-carboxylic acid

Prepare in an analogous fashion to Example 1, but using Intermediateacid 11 (1 eq.) in place of Intermediate acid 1 and rac-methyl6-aminospiro[3.3]heptane-2-carboxylate hydrochloride (1.5 eq.) in placeof Intermediate amine 1 in Step 1. ESI⁺: M+1: 491. ESI⁻: M−1: 489.

Example 23:rac-6-(6-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiroheptane-2-carboxylic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 12 (1 eq.) in place of Intermediate acid 1 and rac-methyl6-aminospiro[3.3]heptane-2-carboxylate hydrochloride (1.5 eq.) in placeof Intermediate amine 1 in Step 1. ESI⁺: M+1: 475. ESI⁻: M−1: 473.

Example 24:rac-6-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid

Prepared in an analogous fashion to Example 1, but using rac-methyl6-aminospiro[3.3]heptane-2-carboxylate hydrochloride (1.5 eq.) in placeof Intermediate amine 1 in Step 1. ESI⁺: M+1: 414. ESI⁻: M−1: 412.

Example 25:rac-6-(1-(4-(difluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 13 (1 eq.) in place of Intermediate acid 1 and rac-methyl6-aminospiro[3.3]heptane-2-carboxylate hydrochloride (1.5 eq.) in placeof Intermediate amine 1 in Step 1. ESI⁺: M+1: 439. ESI⁻: M−1: 437.

Example 26:2-(4-(1-(4-(difluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[2.1.1]hexan-1-yl)aceticacid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 13 (1 eq.) in place of Intermediate acid 1 and intermediate amine 3(1.5 eq.) in place of Intermediate amine 1 in Step 1. ESI⁺: M+1: 439.EST: M−1: 437.

Example 27:2-(3-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclopentan-1-yl)acetic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 9 (1 eq.) in place of Intermediate acid 1 in Step 1. ESI⁺: M+1:461. ESI⁻: M−1: 459.

Example 28:2-(4-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclohexan-1-yl)acetic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 9 (1 eq.) in place of Intermediate acid 1 and intermediate amine 3(1.5 eq.) in place of in intermediate amine 1 in Step 1. ESI⁺: M+1: 475.ESI⁻: M−1: 473.

Example 29:2-(4-(1-((4-(pentafluorothiol)phenyl)methyl)-1H-indole-7-carboxamido)bicyclohexan-1-yl)acetic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 15 (1 eq.) in place of Intermediate acid 1 and intermediate amine 3(1.5 eq.) in place of in intermediate amine 1 in Step 1. ESI⁺: M+1: 515.ESI⁻: M−1: 513.

Example 30:rac-6-(1-((4-(pentafluorothiol)phenyl)methyl)-1H-indole-7-carboxamido)spiroheptane-2-carboxylic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 15 (1 eq.) in place of Intermediate acid 1 and rac-methyl6-aminospiro[3.3]heptane-2-carboxylate hydrochloride (1.5 eq.) in placeof Intermediate amine 1 in Step 1. ESI⁺: M+1: 515. ESI⁻: M−1: 513.

Example 31:rac-6-(1-(4-(difluoromethyl)benzyl)-4-fluoro-1H-indole-7-carboxamido)spiroheptane-2-carboxylic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 14 (1 eq.) in place of Intermediate acid 1 and rac-methyl6-aminospiro[3.3]heptane-2-carboxylate hydrochloride (1.5 eq.) in placeof Intermediate amine 1 in Step 1. ESI⁺: M+1: 457. ESI⁻: M−1: 455.

Example 32:2-(3-(1-(4-(difluoromethyl)benzyl)-4-fluoro-1H-indole-7-carboxamido)bicyclopentan-1-yl)acetic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 14 (1 eq.) in place of Intermediate acid 1 in Step 1. ESI⁺: M+1:443. ESI⁻: M−1: 441.

Example 33:2-(3-(5-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclopentan-1-yl)acetic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 9 (1 eq.) in place of Intermediate acid 1 in Step 1. ESI⁺: M+1:461. ESI⁻: M−1: 459.

Example 34:2-(3-(1-([1,1′-biphenyl]-4-ylmethyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)aceticacid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 16 (1 eq.) in place of Intermediate acid 1 in Step 1. ESI⁺: M+1:451. ESI⁻: M−1: 449.

Example 35:2-(3-(1-([1,1′-biphenyl]-4-ylmethyl)-4-fluoro-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 17 (1 eq.) in place of Intermediate acid 1 in Step 1. ESI⁺: M+1:469. ESI⁻: M−1: 467.

Example 36:2-(3-(1-([1,1′-biphenyl]-4-ylmethyl)-1H-indazole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)aceticacid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 18 (1 eq.) in place of Intermediate acid 1 in Step 1. ESI⁺: M+1:452. ESI⁻: M−1: 450.

Example 37:2-(3-(1-(4-(trifluoromethoxy)benzyl)-1H-indazole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)aceticacid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 19 (1 eq.) in place of Intermediate acid 1 in Step 1. ESI⁺: M+1:460. ESI⁻: M−1: 458.

Example 38:2-(3-(4-fluoro-1-(4-iodobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid

Prepared in an analogous fashion to Example 1, but using Intermediateacid 20 (1 eq.) in place of Intermediate acid 1 in Step 1. ESI⁺: M+1:519. ESI⁻: M−1: 517.

Example 39:2-(3-(4-fluoro-1-(4-(pyridine-4-yl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid

2-(3-(4-Fluoro-1-(4-iodobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid (1 eq., Example 38), 4-pyridinylboronicacid (3 eq.), and XPhos-Palladium 3^(rd) generation precatalyst complex(0.1 eq.) were combined in dioxane (0.14 M). The resulting yellowsolution was deoxygenated via sub-surface purging with a stream ofnitrogen for 15 min. Potassium phosphate (3 eq. 2 N aq. solution) wasthen added to the reaction mixture and the resulting biphasic solutionwas further deoxygenated via sub-surface purging with a stream ofnitrogen for another 15 min. The reaction vessel was then tightly sealedand heated at 80° C.; for 12 h. The resulting mixture was cooled to RTand then directly subjected to rpHPLC (C₁₈, 9:1 (v/v) H₂O: MeCN+0.1%formic acid to MeCN+0.1% formic acid). Fractions with the product werecombined and concentrated in vacuo to afford the title compound as anoff-white solid (53% yield). ESI⁺: M+1: 470. EST: M−1: 468.

Example 40:2-(3-(4-fluoro-1-(4-morpholinobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid

2-(3-(4-Fluoro-1-(4-iodobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid (1 eq., Example 38), morpholine (2 eq.),RuPhos-Palladium 2^(nd) generation precatalyst complex (0.05 eq.) andsodium tert-pentoxide (2.5 eq.) were combined in dioxane (0.055 M). Theresulting orange-red suspension was deoxygenated via sub-surface purgingwith a stream of nitrogen for 15 min. The reaction vessel was thentightly sealed and heated at 80° C. for 12 h. The resulting mixture wascooled to RT and then directly subjected to rpHPLC (C₁₈, 9:1 (v/v) H₂O:MeCN+0.1% formic acid to MeCN+0.1% formic acid). Fractions with theproduct were combined and concentrated in vacuo to afford the titlecompound as an off-white solid (53% yield). ESI⁺: M+1: 478. ESI⁻:M−1:476.

The embodiments described above are intended to be merely exemplary andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the claimed subject matter and areencompassed by the appended claims.

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt, solvate, solvate of the salt,hydrate, a single stereoisomer, a mixture of stereoisomers, a racemicmixture of stereoisomers, or prodrug thereof, wherein: Ar is an aryl ora heteroaryl, wherein said aryl and said heteroaryl are each optionallysubstituted with 1 to 3 substituents independently selected from: (a)C₁-C₆ alkyl, (b) C₃-C₇ cycloalkyl, (c) heterocycle, (d) aryl, (e)heteroaryl, (f) halogen, (g) CN, (h) OR^(b), (i) N(R^(b))C(═O)R^(c), (j)C(═O)N(R^(b))(R^(c)), (k) S(═O)_(m)R^(b), (l) S(═O)₂N(R^(b))(R^(c)), (m)N(R^(b))S(═O)₂R^(c), (n) SF₅; and (o) C₁-C₆ haloalkyl W is selectedfrom: (a) C(═O)OR⁵, (b) C(═O)NHOH, (c) S(═O)₂NHR^(b), (d)S(═O)₂NHC(═O)R^(b), (e) NHC(═O)NHSO₂R^(b), (f) 1H-tetrazole, (g)1,2,4-oxadiazol-5(4H)one, (h) 1,2,4-thiadiazol-5(4H)one, (i)1,2,4-oxadiazole-5(4H)-thione, (j) 1,2,4-triazole-5(4H)-one, (k)tetrazol-5(4H)-one, and (l) C(═O)NHS(═O)₂R^(b); X¹, X², X³, X⁴, and X⁵are each independently N or CR^(a), wherein not more than 2 of X¹, X²,X³, X⁴, and X⁵ are N; Y is selected from: (a) a bond, (b) (CH₂)_(n)wherein 1 to 4 hydrogen atoms may be replaced by R^(a′), (c) O, and (d)NR^(b); Z is (CH₂)_(n), wherein 1 to 4 hydrogen atoms may be replaced byR^(a′); R¹ and R² are independently selected from: (a) H, (b) C₁-C₆alkyl, (c) C₃-C₆ cycloalkyl, and (d) C₁-C₆ haloalkyl; wherein R² is notH; or R¹ and R² taken together represent —(CH₂)_(n)—,—(CH₂)_(n)O(CH₂)_(p)—, —(CH₂)_(n)NR^(b)(CH₂)_(p)— or—(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—; R³ and R⁴ are independently selectedfrom: (a) H, (b) C₁-C₆ alkyl, (c) C₃-C₆ cycloalkyl, (d) aryl, (e)heteroaryl, (f) halogen, (g) C₁-C₆ haloalkyl; or R³ and R⁴ takentogether represent —(CH₂)_(n)—, —(CH₂)_(n)O(CH₂)_(p)—,—(CH₂)_(n)NR^(b)(CH₂)_(p)— or —(CH₂)_(n)S(═O)_(m)(CH₂)_(p)—; or R¹, R²,R³ and R⁴ above are selected as follows: R¹ is selected from H, C₁-C₆alkyl, C₃-C₆ cycloalkyl, and C₁-C₆ haloalkyl; R³ and R² taken togetherrepresent (CH₂)_(n), (CH₂)_(n)O(CH₂)_(p), (CH₂)_(n)NR^(b)(CH₂)_(p), or(CH₂)_(n)S(═O)_(m)(CH₂)_(p); and R⁴ is selected from H, C₁-C₆ alkyl,C₃-C₆ cycloalkyl, aryl, heteroaryl, halogen and C₁-C₆ haloalkyl; R⁵ isselected from (a) H, (b) C₁-C₆ alkyl, (c) aryl, (d) aralkyl, (e)CH(R⁷)OC(═O)R⁸, (f) CH(R⁷)OC(═O)OR⁸, and (g) a(5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl group having the followingformula:

wherein R⁶ is C₁-C₆ alkyl; R⁷ is hydrogen or C₁-C₆ alkyl; R⁸ is C₁-C₆alkyl or C₃-C₆-cycloalkyl; R^(a) is selected from: (a) H, (b) C₁-C₆alkyl, (c) halogen, (d) aryl, (e) OR^(b), (f) cyano, (g) heteroaryl, (h)C₃-C₆ cycloalkyl, and (i) C₁-C₆ haloalkyl; R^(a′) is selected from: (a)cyano, (b) C₁-C₆ alkyl, (c) halogen, (d) aryl, (e) OR^(b), (f)heteroaryl, (g) C₃-C₆ cycloalkyl, and (h) C₁-C₆ haloalkyl; R^(b) andR^(c) are independently selected from: (a) H, (b) C₁-C₆ alkyl, (c) aryl,(d) heteroaryl, (e) C₃-C₆ cycloalkyl, and (f) C haloalkyl; or R^(b) andR^(c) taken together with the N to which they are both attached form a3- to 6-membered heterocycle optionally having an additional heteroatomselected from N, O and S; m is 0, 1, or 2; n is 1, 2 or 3; and p is 1, 2or
 3. 2. A compound of claim 1 wherein Ar is aryl or heteroaryloptionally substituted with 1 to 3 substituents independently selectedfrom: (a) halogen, (b) cyano, (c) C₁-C₆ alkyl, (d) SF₅, (e) C₁-C₆haloalkyl, (f) OR^(b) wherein R^(b) is C₁-C₆ alkyl, aryl, heteroaryl,C₃-C₆ cycloalkyl or C₁-C₆ haloalkyl; (g) heterocycle, (h) aryl, and (i)heteroaryl.
 3. A compound of claim 1 or claim 2 wherein Ar is phenyl. 4.A compound any one of claims 1 to 3 wherein each of X¹, X², X³, X⁴ andX⁵ is independently C—R^(a), or one of X¹, X², X³, X⁴ and X⁵ is N, andthe others are each independently C—R^(a).
 5. A compound of claim 4wherein each of X¹, X², X³, X⁴ and X⁵ is independently C—R^(a).
 6. Acompound of any of claims 1 to 5 wherein R^(a) is H or a halogen atom.7. A compound of any of claims 1 to 6 wherein W is selected from thegroup consisting of: (a) CO₂H; and (b) 1H-tetrazole.
 8. A compound ofany of claims 1 to 7 wherein Z is —CH₂—.
 9. A compound of any of claims1 to 8 wherein Y is a bond or —CH₂—.
 10. A compound of any of claims 1to 9 wherein R¹ and R² taken together represent —CH₂—, —CH₂CH₂— or—CH₂CH₂CH₂—.
 11. A compound of any of claims 1 to 8 wherein Y is —CH₂—,and R³ and R² taken together represent —CH₂—, —CH₂CH₂— or —CH₂CH₂CH₂—.12. A compound of claim 1 having the Formula Ia:

or a pharmaceutically acceptable salt, solvate, solvate of the salt,hydrate, a single stereoisomer, a mixture of stereoisomers, a racemicmixture of stereoisomers, or prodrug thereof, wherein Ar is phenyloptionally substituted with 1 to 3 substituents independently selectedfrom: (a) halogen, (b) cyano, (c) C₁-C₆ alkyl, (d) SF₅, (e) C₁-C₆haloalkyl, (f) OR^(b) wherein R^(b) is C₁-C₆ alkyl, aryl, heteroaryl,C₃-C₆ cycloalkyl or C₁-C₆ haloalkyl, (g) heterocycle, (h) aryl, and (i)heteroaryl; each X¹, X², X³, X⁴ and X⁵ is independently C—R^(a), or oneof X¹, X², X³, X⁴ and X⁵ is N, and the others are each independentlyC—R^(a); W is selected from: (a) CO₂H and (b) 1H-tetrazole; Y is a bondor —CH₂—; n is 1 or 2; R³ and R⁴ are independently selected: (a) H, (b)C₁-C₃ alkyl, and (c) C₁-C₃ haloalkyl; R^(a) is selected from: (a) H and(b) halogen.
 13. A compound of any of claims 1 to 12 wherein Y is abond, and n is
 1. 14. A compound of claim 1 having the Formula Ib:

or a pharmaceutically acceptable salt, solvate, solvate of the salt,hydrate, a single stereoisomer, a mixture of stereoisomers, a racemicmixture of stereoisomers, or prodrug thereof, wherein Ar is phenyloptionally substituted with 1 to 3 substituents independently selectedfrom: (a) halogen, (b) cyano, (c) C₁-C₆ alkyl, (d) SF₅, (e) C₁-C₆haloalkyl, (f) OR^(b) wherein R^(b) is C₁-C₆ alkyl, aryl, heteroaryl,C₃-C₆ cycloalkyl or C₁-C₆ haloalkyl, (g) heterocycle, (h) aryl, and (i)heteroaryl; each X¹, X², X³, X⁴ and X⁵ is independently C—R^(a), or oneof X¹, X², X³, X⁴ and X⁵ is N, and the others are each independentlyC—R^(a); W is selected from: (a) CO₂H and (b) 1H-tetrazole; n is 1 or 2;R⁴ is selected from: (a) H, (b) C₁-C₃ alkyl, and (c) C₁-C₃ haloalkyl;R^(a) is selected from: (a) H and (b) halogen.
 15. A compound of claim14 wherein n is
 1. 16. A compound of claim 1 having the Formula Ic orId:

or a pharmaceutically acceptable salt, solvate, solvate of the salt,hydrate, a single stereoisomer, a mixture of stereoisomers, a racemicmixture of stereoisomers, or prodrug thereof, wherein each X¹, X², X³,X⁴ and X⁵ is independently C—R^(a), or one of X¹, X², X³, X⁴ and X⁵ isN, and the others are each independently C—R^(a); R^(a) is selectedfrom: (a) H and (b) halogen; R^(d) is selected from: (a) CN, (b) C₁-C₃alkyl, (c) SF₅, (d) C₁-C₃ haloalkyl, (e) OR^(b) wherein R^(b) is C₁-C₆alkyl, aryl, heteroaryl, C₃-C₆ cycloalkyl or C₁-C₆ haloalkyl, (f)heterocycle, (g) aryl, and (h) heteroaryl.
 17. A compound of any ofclaims 1 to 16 wherein each X¹, X², X³, X⁴ and X⁵ is CH; or one of X¹,X², X³, X⁴ and X⁵ is C—R^(a) and the others are CH, and R^(a) ishalogen.
 18. A compound of claim 1 selected from:2-(3-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)aceticacid;2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)aceticacid;2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)aceticacid;2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)aceticacid;2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)aceticacid;2-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)aceticacid;2-(3-(1-((4-(trifluoromethyl)phenyl)methyl-d₂)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)aceticacid;6-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(5)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-b]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(5)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[3,2-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(5)-6-(1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo[2,3-c]pyridine-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;6-(1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indazole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;6-(1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(R)-6-(1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(S)-6-(1-(4-(trifluoromethyl)benzyl)-1H-benzo[d]imidazole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;3-(3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)propanoicacid;3-(3-methyl-3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)cyclobutyl)propanoicacid;cis-3-(3-methyl-3-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)cyclobutyl)propanoicacid;N-(3-(2-oxo-2-(phenylsulfonamido)ethyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide;N-(3-((3-(phenylsulfonyl)ureido)methyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide;N-(3-((1H-tetrazol-5-yl)methyl)bicyclo[1.1.1]pentan-1-yl)-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamide;2-(4-(1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[2.1.1]hexan-1-yl)aceticacid;6-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(R)-6-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(S)-6-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;6-(5-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(R)-6-(5-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(S)-6-(5-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;6-(5-chloro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(R)-6-(5-chloro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(S)-6-(5-chloro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;6-(6-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(R)-6-(6-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(S)-6-(6-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;6-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(R)-6-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(S)-6-(1-(4-cyanobenzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;6-(1-(4-(difluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(R)-6-(1-(4-(difluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(S)-6-(1-(4-(difluoromethyl)benzyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;2-(4-(1-(4-(difluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[2.1.1]hexan-1-yl)aceticacid;2-(3-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)aceticacid;2-(4-(4-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[2.1.1]hexan-1-yl)aceticacid;2-(4-(1-((4-(pentafluorothiol)phenyl)methyl)-1H-indole-7-carboxamido)bicyclo[2.1.1]hexan-1-yl)aceticacid;6-(1-((4-(pentafluorothiol)phenyl)methyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(R)-6-(1-((4-(pentafluorothiol)phenyl)methyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(S)-6-(1-((4-(pentafluorothiol)phenyl)methyl)-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;6-(1-(4-(difluoromethyl)benzyl)-4-fluoro-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(R)-6-(1-(4-(difluoromethyl)benzyl)-4-fluoro-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;(S)-6-(1-(4-(difluoromethyl)benzyl)-4-fluoro-1H-indole-7-carboxamido)spiro[3.3]heptane-2-carboxylicacid;2-(3-(1-(4-(difluoromethyl)benzyl)-4-fluoro-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)aceticacid;2-(3-(5-fluoro-1-(4-(trifluoromethyl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)aceticacid;2-(3-(1-([1,1′-biphenyl]-4-ylmethyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid;2-(3-(1-([1,1′-biphenyl]-4-ylmethyl)-4-fluoro-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid;2-(3-(1-([1,1′-biphenyl]-4-ylmethyl)-1H-indazole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid;2-(3-(1-(4-(trifluoromethoxy)benzyl)-1H-indazole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid;2-(3-(4-fluoro-1-(4-iodobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid;2-(3-(4-fluoro-1-(4-(pyridine-4-yl)benzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid; and2-(3-(4-fluoro-1-(4-morpholinobenzyl)-1H-indole-7-carboxamido)bicyclo[1.1.1]pentan-1-yl)acetic acid; or a pharmaceutically acceptable salt, solvate, solvate ofthe salt or prodrug thereof.
 19. A pharmaceutical composition comprisinga compound of any of claims 1 to 18, or a pharmaceutically acceptablesalt, solvate, solvate of the salt, hydrate, a single stereoisomer, amixture of stereoisomers, a racemic mixture of stereoisomers, or prodrugthereof, and a pharmaceutically acceptable carrier.
 20. A method for thetreatment of cancer comprising administering to a patient in needthereof a compound of any of claims 1 to 18 or the pharmaceuticalcomposition of claim
 19. 21. The method of claim 20 wherein said canceris selected from glioblastoma, bone cancer, head and neck cancer,melanoma, basal cell carcinoma, squamous cell carcinoma, adenocarcinoma,oral cancer, esophageal cancer, gastric cancer, intestinal cancer, coloncancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma,pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breastcancer, and prostate cancer.
 22. The method of claim 20 or claim 21wherein said cancer is selected from colon cancer, bladder cancer,hepatocellular carcinoma, pancreatic cancer, ovarian cancer, cervicalcancer, lung cancer, breast cancer, and prostate cancer.
 23. The methodof any of claims 20 to 22 wherein said treatment further comprises anadditional agent selected from an anti-PD-1 antibody and an anti-PD-L1antibody.